MaltSci 麦伴科研

Appearance

Popular Reports / Cancer Research

This report is written by MaltSci based on the latest literature and research findings

What is the role of tumor microenvironment in cancer progression? ​

Abstract ​

Cancer is a leading cause of morbidity and mortality globally, with the tumor microenvironment (TME) playing a crucial role in its progression and therapeutic resistance. The TME comprises various non-cancerous cells, including cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and extracellular matrix (ECM) components, which collectively create a supportive niche for tumor growth and dissemination. Recent insights have highlighted the dynamic interactions between tumor cells and TME components, revealing that these interactions can promote tumorigenesis, facilitate metastasis, and influence the efficacy of therapeutic interventions. This review synthesizes current literature on the TME's contributions to cancer biology, emphasizing the roles of CAFs in inflammation and metabolic reprogramming, immune cell infiltration in shaping the immune landscape, endothelial cells in angiogenesis, and ECM remodeling in tumor progression. Additionally, we explore the therapeutic implications of targeting the TME, discussing current strategies in clinical trials and potential future directions for research. Understanding the multifaceted roles of the TME is essential for developing novel therapeutic strategies aimed at disrupting these supportive interactions, ultimately contributing to improved patient outcomes in cancer treatment.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Components of the Tumor Microenvironment
    • 2.1 Cancer-Associated Fibroblasts
    • 2.2 Immune Cell Infiltration
    • 2.3 Endothelial Cells and Angiogenesis
    • 2.4 Extracellular Matrix and its Role
  • 3 Interactions between Tumor Cells and the Microenvironment
    • 3.1 Cell-Cell Interactions
    • 3.2 Signaling Pathways Involved
    • 3.3 Impact on Tumor Metabolism
  • 4 The Role of the TME in Cancer Progression
    • 4.1 Tumor Growth and Survival
    • 4.2 Metastasis and Tumor Spread
    • 4.3 Treatment Resistance
  • 5 Therapeutic Implications of Targeting the TME
    • 5.1 Current Strategies in Clinical Trials
    • 5.2 Future Directions for Research
    • 5.3 Challenges in Targeting the TME
  • 6 Conclusion

1 Introduction ​

Cancer remains one of the leading causes of morbidity and mortality worldwide, with complex biological processes underpinning its initiation, progression, and metastasis. Traditionally, research has focused on the genetic and molecular alterations within cancer cells themselves; however, recent insights have illuminated the critical role of the tumor microenvironment (TME) in modulating these processes. The TME comprises a diverse array of non-cancerous cells, including cancer-associated fibroblasts, immune cells, endothelial cells, and components of the extracellular matrix (ECM), which collectively create a supportive niche for tumor growth and dissemination [1][2]. This environment not only influences tumor cell behavior but also affects the efficacy of therapeutic interventions, making it a crucial target for cancer treatment strategies [3][4].

Understanding the TME is of paramount importance as it contributes to various hallmarks of cancer, including sustained proliferative signaling, evasion of growth suppressors, and the ability to induce angiogenesis and metastasis [5][6]. The dynamic interactions between tumor cells and the TME components can either promote tumorigenesis or inhibit therapeutic responses, leading to challenges such as drug resistance and treatment failure [7][8]. Therefore, elucidating the multifaceted roles of the TME is essential for the development of novel therapeutic strategies aimed at disrupting these supportive interactions [4][9].

The current review aims to synthesize the existing literature on the TME's contributions to cancer progression and therapeutic resistance. We will begin by exploring the various cellular and molecular components that constitute the TME, including cancer-associated fibroblasts, immune cell infiltration, endothelial cells, and the ECM, as outlined in Section 2 of the report. This will be followed by an examination of the interactions between tumor cells and their microenvironment in Section 3, where we will discuss cell-cell interactions, signaling pathways involved, and the impact on tumor metabolism.

In Section 4, we will delve into the specific roles of the TME in cancer progression, focusing on tumor growth and survival, metastasis, and treatment resistance. Finally, Section 5 will highlight the therapeutic implications of targeting the TME, including current strategies being explored in clinical trials, future directions for research, and the challenges faced in effectively targeting this complex environment. Through this comprehensive review, we aim to provide a clearer understanding of the TME's role in cancer biology and its potential as a therapeutic target, ultimately contributing to improved patient outcomes in cancer treatment.

2 Components of the Tumor Microenvironment ​

2.1 Cancer-Associated Fibroblasts ​

The tumor microenvironment (TME) plays a pivotal role in cancer progression, characterized by a complex interplay of various cellular and non-cellular components. Among these components, cancer-associated fibroblasts (CAFs) are crucial players that significantly influence tumor dynamics. CAFs are the predominant cell type within the TME and are involved in multiple processes that contribute to tumor initiation, growth, invasion, and metastasis.

CAFs serve as the main suppliers of extracellular matrix (ECM) molecules and are vital contributors to inflammation within the TME. They secrete a range of growth factors, cytokines, and chemokines that not only support tumor cell proliferation but also facilitate angiogenesis and immune cell reprogramming. This multifaceted contribution of CAFs underscores their role in promoting cancer progression and therapeutic resistance [10].

The heterogeneity of CAFs is a critical aspect that complicates their functional characterization. CAFs exhibit diversity in their origin, phenotype, and functional capabilities, which can vary significantly across different tumor types and even within a single tumor. This heterogeneity hampers the development of targeted therapies aimed at CAFs, as the specific roles of different CAF populations in cancer progression are not yet fully understood [11].

In the context of specific cancers, such as breast cancer, evidence indicates that CAFs are actively involved in various stages of tumor development, including initiation, proliferation, invasion, and metastasis. They are also implicated in metabolic reprogramming within the TME and contribute to resistance against therapeutic interventions [11]. Similarly, in gastric cancer, CAFs have been identified as significant risk factors for poor prognosis and are linked to chemoresistance [12].

The interactions between CAFs and cancer cells are mediated through various signaling pathways and molecular exchanges. For instance, CAFs can influence the behavior of cancer cells by altering their metabolic pathways and promoting a pro-inflammatory microenvironment that favors tumor growth. The role of microRNAs (miRNAs) in this communication is increasingly recognized, as they can modulate the phenotypic characteristics of CAFs and enhance their tumor-promoting abilities [13].

Furthermore, the TME, including the contributions of CAFs, has been shown to facilitate immune evasion by creating an immunosuppressive environment. This interplay not only supports tumor survival and growth but also complicates the efficacy of immunotherapies [12].

In summary, the tumor microenvironment, particularly through the actions of cancer-associated fibroblasts, plays a critical role in cancer progression by supporting tumor growth, facilitating metastasis, and contributing to therapeutic resistance. Understanding the complex dynamics of CAFs within the TME is essential for developing effective cancer therapies and improving patient outcomes.

2.2 Immune Cell Infiltration ​

The tumor microenvironment (TME) plays a crucial role in cancer progression, acting as a dynamic and complex network that encompasses various cellular and non-cellular components. The TME is not merely a passive background for tumor cells; it actively influences tumor behavior through intricate interactions between cancer cells and surrounding non-malignant cells, including immune cells, fibroblasts, and endothelial cells.

Immune cell infiltration is a significant aspect of the TME, with various immune cell types contributing to tumor development and progression. Tumor-infiltrating immune cells, such as myeloid-derived suppressor cells (MDSCs), macrophages, and lymphocytes, can exhibit both tumor-promoting and tumor-inhibiting effects. For instance, MDSCs are known to foster tumor growth and metastasis by suppressing the immune response and creating an immunosuppressive microenvironment, thereby allowing cancer cells to evade immune detection [14].

The inflammatory TME is a key regulator of carcinogenesis, where tumor-associated immune cells, including myeloid cells and lymphocytes, adopt a tumor-supportive phenotype due to their interactions with tumor cells. This transition is influenced by microenvironmental factors such as inflammation and hypoxia, which are pivotal in shaping the immune cell landscape within tumors [15]. Moreover, the availability of nutrients, such as iron, can further modulate the polarization and function of infiltrating immune cells, impacting tumor growth and the immune response [15].

The interplay between immune cells and tumor cells is complex and multifaceted, leading to different activation phenotypes among infiltrating immune cells, which can vary in their functional characteristics and plasticity. This functional heterogeneity is crucial in determining the overall tumor outcome, as specific immune cell types may either inhibit or promote tumor progression [15].

Additionally, the TME is composed of various cellular components, including cancer-associated fibroblasts, which also play a significant role in tumor initiation and progression. These fibroblasts interact with immune cells and tumor cells, influencing their behavior and contributing to the creation of a supportive niche for cancer cell proliferation [3].

The immune contexture within tumors—characterized by the type, density, location, and organization of immune cells—has been identified as a major determinant of tumor characteristics and patient outcomes. For example, in non-small cell lung cancer, the presence and organization of tumor-infiltrating lymphocytes are critical for understanding tumor behavior and guiding treatment strategies [16].

In summary, the tumor microenvironment, particularly through immune cell infiltration, plays a pivotal role in cancer progression by shaping tumor behavior, influencing immune responses, and determining therapeutic outcomes. Understanding these interactions is essential for developing effective cancer therapies and improving patient stratification for treatment. The complexity of the TME underscores the need for novel therapeutic strategies that target both tumor cells and their surrounding environment [17][18].

2.3 Endothelial Cells and Angiogenesis ​

The tumor microenvironment (TME) plays a critical role in cancer progression, comprising various cellular components that interact dynamically to influence tumor behavior. Among these components, endothelial cells (ECs) are pivotal in the processes of angiogenesis and tumor progression.

Endothelial cells contribute significantly to tumor angiogenesis, which is essential for providing the growing tumor with necessary nutrients and oxygen. This process is characterized by the formation of new blood vessels from pre-existing ones, as well as the recruitment of bone marrow-derived endothelial progenitor cells (Collet et al., 2012)[19]. The tumor microenvironment, which includes not only tumor cells but also stromal cells such as fibroblasts, macrophages, and ECs, creates a conducive environment for tumor growth and metastasis. It is well established that ECs are involved in regulating the interactions between circulating blood cells, tumor cells, and the extracellular matrix, thus influencing leukocyte recruitment, tumor cell behavior, and metastasis formation (Ji et al., 2023)[20].

Hypoxia, a common feature of the TME, plays a crucial role in modulating these interactions. Under hypoxic conditions, tumor cells secrete factors that promote angiogenesis and vasculogenesis, further driving tumor progression (Collet et al., 2012)[19]. Additionally, the phenomenon of endothelial-to-mesenchymal transition (EndoMT) allows ECs to alter their phenotype, contributing to the tumor's invasive capabilities and resistance to therapy (Watabe et al., 2023)[21].

The interplay between cancer cells and ECs involves a complex signaling network where both cell types release various factors that facilitate angiogenesis, metastasis, and potentially drug resistance (Choi & Moon, 2018)[22]. These interactions underscore the importance of targeting not only the tumor cells but also the components of the TME, particularly ECs, to improve therapeutic outcomes.

Recent studies have also highlighted the role of angiocrine factors—secreted by ECs—that influence tumor behavior beyond mere angiogenesis. These factors can modulate the immune response, promote cancer cell survival, and facilitate metastasis (Oginga Oria & Erler, 2023)[23]. Therefore, understanding the functional contributions of ECs within the TME is crucial for developing novel therapeutic strategies aimed at disrupting these interactions and ultimately controlling tumor progression.

In summary, the tumor microenvironment, particularly through the role of endothelial cells, is integral to cancer progression. It facilitates angiogenesis, modifies tumor cell behavior, and influences metastasis, making it a vital target for therapeutic intervention.

2.4 Extracellular Matrix and its Role ​

The tumor microenvironment (TME) plays a critical role in cancer progression, acting as a complex ecosystem that includes both cellular and non-cellular components. One of the key components of the TME is the extracellular matrix (ECM), which is a dynamic network of proteins and other molecules that provides structural and biochemical support to surrounding cells. The interactions between cancer cells and the ECM significantly influence various aspects of tumor development, including growth, invasion, and metastasis.

The ECM is not merely a passive scaffold; it actively participates in the regulation of cellular functions. For instance, the ECM influences cancer cell proliferation, survival, migration, and differentiation. Changes in the composition and mechanical properties of the ECM, such as increased stiffness, have been associated with enhanced tumor progression. This alteration can promote cancer cell behaviors that lead to metastasis by activating signaling pathways through mechanotransduction—where cells convert mechanical stimuli into biochemical signals[24].

Moreover, the ECM undergoes extensive remodeling during tumor development. This remodeling process can alter the availability of growth factors and cytokines, thereby modulating the tumor microenvironment and affecting immune cell infiltration and activity. For example, cancer-associated fibroblasts and immune cells within the TME can interact with the ECM, producing proteolytic enzymes that further remodel the matrix, facilitating tumor invasion and the establishment of metastases[4][25].

The ECM also serves as a reservoir for various signaling molecules, which can influence cancer cell behavior. For instance, matricellular proteins, which are part of the ECM, can modulate cell signaling pathways that affect tumor cell plasticity and response to therapy[26][27]. The presence of these proteins and their interaction with cell surface receptors can lead to changes in the tumor microenvironment that support cancer cell survival and proliferation[28].

In addition, the ECM's biochemical and biomechanical properties play a significant role in the establishment of a suppressive microenvironment. For example, tumor-associated macrophages and cancer-associated fibroblasts can create a niche that inhibits effective immune responses, further contributing to cancer progression[29].

Furthermore, the ECM is increasingly recognized as a potential source of biomarkers for cancer diagnosis and prognosis. Alterations in ECM components can reflect the tumor's behavior and may provide insights into the effectiveness of therapeutic strategies[30].

In summary, the tumor microenvironment, particularly the extracellular matrix, is integral to cancer progression. It not only supports tumor architecture but also actively influences cellular behaviors and interactions that drive tumor growth, invasion, and metastasis. Understanding the intricate dynamics of the ECM and its role in the TME is crucial for developing novel therapeutic strategies aimed at disrupting these cancer-promoting interactions[27][31].

3 Interactions between Tumor Cells and the Microenvironment ​

3.1 Cell-Cell Interactions ​

The tumor microenvironment (TME) plays a critical role in cancer progression through complex interactions between tumor cells and various cellular and non-cellular components. It comprises a diverse array of cells, including immune cells, fibroblasts, endothelial cells, and components of the extracellular matrix (ECM), which together create a dynamic and supportive environment for tumor growth and metastasis.

Cell-cell interactions within the TME significantly influence tumor behavior. For instance, tumor-associated macrophages (TAMs) can adopt a polarized state that promotes tumor progression and metastasis. These M2-polarized macrophages are known to secrete various cytokines and growth factors that enhance cancer cell survival, proliferation, and invasiveness [32]. Similarly, the interaction between cancer cells and fibroblasts can lead to the formation of a supportive stroma that fosters tumor growth and resistance to therapies [33].

Moreover, the mechanical properties of the TME, such as stiffness and ECM composition, can trigger mechanotransduction pathways in cancer cells, leading to changes in their behavior, including enhanced migration and invasion [34]. The presence of immune cells, particularly in an inflammatory context, can also modulate tumor cell responses. For example, neutrophils can interact with other immune cells and tumor cells, influencing the balance between pro-tumor and anti-tumor immune responses [35].

The TME is not merely a passive environment; it actively participates in tumor progression through paracrine signaling. Tumor cells release factors that can alter the behavior of stromal cells, creating a feedback loop that supports tumor growth [9]. This interplay can lead to the establishment of a pro-tumorigenic niche, where cancer cells thrive and develop resistance to therapies [5].

Furthermore, the TME contributes to the phenomenon of immune evasion, where tumor cells exploit their microenvironment to escape immune surveillance. The chronic inflammation induced by the TME can create an immunosuppressive environment that allows tumors to grow unchecked [36].

In summary, the tumor microenvironment is a crucial player in cancer progression, affecting tumor cell behavior through a variety of mechanisms, including direct cell-cell interactions, signaling pathways activated by mechanical properties, and the modulation of immune responses. Understanding these interactions is essential for developing effective therapeutic strategies aimed at targeting the TME to improve cancer treatment outcomes [4][5][34].

3.2 Signaling Pathways Involved ​

The tumor microenvironment (TME) plays a pivotal role in cancer progression through complex interactions between tumor cells and various cellular and non-cellular components within the surrounding stroma. This dynamic and intricate network includes immune cells, fibroblasts, endothelial cells, and extracellular matrix (ECM) components, all of which contribute to the tumor's behavior and therapeutic responses.

Tumor cells actively recruit stromal cells, which provide essential growth signals and metabolites necessary for tumor proliferation and metastasis. This recruitment is facilitated through various signaling pathways that are activated in response to tumor-derived factors. For instance, the interaction between cancer cells and the microenvironment leads to reciprocal signaling, whereby tumor cells influence the behavior of stromal cells, which in turn modulate tumor cell functions, creating a feed-forward loop that enhances tumor growth and invasive capabilities [1].

Signaling pathways involved in these interactions include paracrine signaling mechanisms that are critical for tumor progression. For example, growth factors such as epidermal growth factor (EGF), transforming growth factor-alpha (TGF-α), and vascular endothelial growth factor (VEGF) are synthesized by both tumor and stromal cells. These factors initiate signaling cascades in tumor cells that promote migration, invasion, and survival [37]. The activation of pathways such as the Wnt/β-catenin signaling is particularly noteworthy, as it is linked to chemoresistance and aggressiveness in colorectal cancer, illustrating how TME-derived signals can dictate tumor cell fate [38].

Moreover, the tumor microenvironment can create a suppressive milieu that aids in immune evasion and resistance to therapies. Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are key players in this context. They can secrete cytokines and other factors that remodel the ECM and create a supportive environment for tumor growth, thereby enhancing metastatic potential and reducing the effectiveness of immunotherapies [29].

The mechanical properties of the TME, such as increased stiffness and altered fluid dynamics, also influence tumor progression. These biomechanical changes can promote malignant transformation and facilitate tumor cell migration and invasion [39]. The interaction of tumor cells with the ECM, through invadopodia and other structures, is crucial for their invasive capabilities [40].

Overall, the interplay between tumor cells and their microenvironment is governed by a complex array of signaling pathways that regulate not only tumor growth and metastasis but also the response to therapies. Targeting these pathways offers a promising avenue for therapeutic intervention, highlighting the importance of understanding the TME in the context of cancer biology and treatment strategies [5].

3.3 Impact on Tumor Metabolism ​

The tumor microenvironment (TME) plays a critical role in cancer progression by influencing various aspects of tumor biology, particularly through its interactions with tumor cells and its impact on tumor metabolism. The TME is a complex and dynamic ecosystem that includes various non-cancerous cells such as fibroblasts, immune cells, endothelial cells, and the extracellular matrix (ECM). These components interact with tumor cells, facilitating processes that promote tumor growth, survival, and metastasis.

One of the primary functions of the TME is to provide a supportive environment for tumor cells. The interactions between tumor cells and stromal cells can lead to metabolic changes that are crucial for cancer progression. For instance, tumor cells often exhibit altered metabolism, characterized by increased glycolysis and changes in nutrient utilization, which are driven by the TME's cellular and biochemical composition [41]. The metabolic plasticity of tumors allows cancer cells to scavenge nutrients effectively, using mechanisms such as autophagy and macropinocytosis, which are supported by the surrounding stromal cells [41].

Furthermore, the TME is known to influence the immune landscape, where cytokines and metabolites produced by stromal cells can promote immune evasion, thereby allowing tumor cells to escape immune surveillance [42]. This immune-modulatory role of the TME is significant, as it not only facilitates tumor growth but also contributes to therapeutic resistance, making it a crucial target for improving cancer treatments [42].

The interplay between cancer-associated fibroblasts (CAFs) and tumor cells is particularly noteworthy. CAFs secrete various factors that enhance tumor cell proliferation and contribute to the metabolic reprogramming of cancer cells [13]. Additionally, miRNAs expressed in CAFs can modulate the communication between fibroblasts and tumor cells, further influencing tumor progression and metastasis [13].

The biomechanical aspects of the TME, such as increased matrix stiffness and interstitial fluid pressure, also play a significant role in tumor progression. These biomechanical forces can alter the behavior of stromal cells and promote tumor invasion [39]. The physical properties of the TME can therefore shape the interactions between tumor and stromal cells, facilitating a microenvironment that is conducive to cancer progression [39].

In summary, the tumor microenvironment is integral to cancer progression through its multifaceted interactions with tumor cells. It not only provides a supportive framework for tumor growth and survival but also influences metabolic processes and immune responses, contributing to the complexity of cancer behavior and treatment resistance. Understanding these interactions is essential for developing effective therapeutic strategies that target both tumor cells and their microenvironment.

4 The Role of the TME in Cancer Progression ​

4.1 Tumor Growth and Survival ​

The tumor microenvironment (TME) plays a pivotal role in cancer progression by influencing tumor growth, survival, and metastasis through complex interactions with cancer cells. The TME is composed of various non-cancerous cells, including fibroblasts, immune cells, endothelial cells, and components of the extracellular matrix (ECM). This intricate network not only supports tumor cells but also actively participates in their malignant behavior.

Cancer cells rely on the TME for essential growth signals and nutrients. For instance, stromal cells within the TME provide tumor cell growth signals and intermediate metabolites, creating a conducive environment for tumor progression and metastasis. This reciprocal communication between cancer cells and the TME enhances the proliferation and invasive capabilities of tumors, as both entities collude to optimize their survival and growth conditions (Yuan et al., 2016; Ariztia et al., 2006).

The TME also contributes to tumor cell survival through mechanisms such as the formation of a protective niche. Host factors within the TME can significantly influence the response of tumors to therapies. For example, cancer-associated fibroblasts and immune cells can create an immunosuppressive environment that enables cancer cells to evade immune detection and resist therapeutic interventions (Gao et al., 2014; Kumari et al., 2021).

Moreover, the physical properties of the TME, such as its stiffness and composition, are crucial for tumor progression. Biomechanical forces generated within the TME can affect how tumor cells interact with their environment, influencing their migratory and invasive behaviors (Shieh, 2011). Increased matrix stiffness and altered ECM composition can promote tumorigenesis and support cancer cell invasion (Emon et al., 2018).

Additionally, the TME can modulate metabolic pathways within tumor cells, affecting their proliferation and survival. The interaction between tumor cells and stromal components can lead to metabolic reprogramming, allowing cancer cells to adapt to and thrive in the hostile conditions often present within the TME (Yang, 2017).

In summary, the tumor microenvironment is integral to cancer progression by providing the necessary support for tumor growth and survival, influencing therapeutic responses, and facilitating metastatic spread. Targeting the TME presents a promising avenue for developing more effective cancer therapies that could disrupt these supportive interactions and improve patient outcomes (Sounni & Noel, 2013; Mittal et al., 2018).

4.2 Metastasis and Tumor Spread ​

The tumor microenvironment (TME) plays a crucial and multifaceted role in cancer progression, particularly in the processes of metastasis and tumor spread. The TME is composed of various cell types, including cancer cells, stromal cells (such as fibroblasts and immune cells), extracellular matrix (ECM), and signaling molecules. These components interact dynamically to influence tumor behavior and response to therapy.

Cancer progression begins with oncogene activation and tumor suppressor gene inactivation, which drive the transformation of normal somatic cells into malignant tumor cells. However, cancer cells alone cannot achieve progression; the TME actively contributes to tumor development and metastasis. Tumor cells recruit stromal cells, which provide essential growth signals, intermediate metabolites, and a supportive environment for tumor growth and dissemination. This reciprocal communication between cancer cells and the TME leads to enhanced proliferation and metastatic potential [1].

The TME is not merely a passive background; it is instrumental in shaping the characteristics of tumors. For instance, the TME creates selective pressures that drive the evolution of cancer cells, leading to heterogeneous populations that can adapt to different microenvironmental conditions. This adaptation includes changes in cellular characteristics that enhance fitness and invasiveness [33]. In particular, factors such as hypoxia, pH, and nutrient availability within the TME can significantly affect cancer cell behavior, including their ability to invade and metastasize [40].

Myeloid-derived suppressor cells (MDSCs) are one of the critical components of the TME that facilitate tumor growth and metastasis. MDSCs can promote an immunosuppressive environment, allowing tumor cells to evade immune surveillance and grow unchecked [14]. Moreover, the inflammatory milieu within the TME, characterized by the presence of cytokines and other pro-inflammatory factors, has been shown to accelerate tumor proliferation, angiogenesis, and metastasis [43].

The ECM, a significant component of the TME, also plays a vital role in tumor progression. It provides structural support and influences cell behavior through biochemical and mechanical signals. Changes in ECM composition and stiffness can facilitate tumor invasion and metastasis, as cancer cells interact with the ECM through various receptors, including integrins [44]. The remodeling of the ECM by cancer-associated fibroblasts (CAFs) is particularly noteworthy, as these cells can create a supportive niche for tumor growth and spread [12].

The spatial organization of cells within the TME further complicates the dynamics of tumor progression. Research suggests that the arrangement and density of different cell types can affect resource availability and functional connectivity, which in turn influences metastatic behavior [33]. The interplay between cancer cells and their microenvironment can lead to the formation of pre-metastatic niches, which prepare distant sites for incoming metastatic cells [5].

In summary, the TME is a complex and dynamic entity that significantly influences cancer progression and metastasis. It does so through various mechanisms, including the recruitment of supportive stromal cells, the provision of growth factors, the remodeling of the ECM, and the establishment of immunosuppressive conditions. Understanding these interactions offers potential therapeutic avenues to target the TME and improve cancer treatment outcomes.

4.3 Treatment Resistance ​

The tumor microenvironment (TME) plays a critical role in cancer progression and treatment resistance through its complex interactions with tumor cells and various cellular and non-cellular components. The TME is not merely a passive backdrop for tumor growth; rather, it actively influences tumor behavior, including initiation, progression, and response to therapies.

Components of the TME, such as stromal cells (including fibroblasts, endothelial cells, and immune cells), the extracellular matrix (ECM), and soluble factors (like cytokines and growth factors), contribute significantly to the maintenance and progression of tumors. For instance, in melanoma, the TME is crucial for tumor maintenance and resistance to therapies, as it comprises not only malignant cells but also supportive stroma and ECM, which interact continuously with tumor cells to modulate their behavior (Kharouf et al. 2023) [45].

The TME creates a dynamic interaction with cancer cells, facilitating their proliferation and survival. It has been shown that various cellular components, such as cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs), can promote tumor growth and metastasis by providing a supportive niche and by evading immune surveillance. CAFs, in particular, have been implicated in drug resistance, as they create a paracrine environment that supports cancer cell survival against therapeutic agents (Kadel et al. 2019) [46].

Moreover, the TME is involved in mediating drug resistance through multiple mechanisms. For example, cancer cells can exploit the TME to activate signaling pathways that protect them from the cytotoxic effects of chemotherapy. This includes the activation of survival pathways that enable cancer cells to enter a dormant state, thereby reducing their susceptibility to treatment (Turlej et al. 2025) [4]. The interplay between tumor cells and their microenvironment can lead to the selection of resistant cell populations, ultimately resulting in treatment failure.

Recent advancements in understanding the TME have led to the exploration of novel therapeutic strategies aimed at targeting the TME itself, alongside traditional cancer treatments. By focusing on the TME, researchers aim to improve the efficacy of existing therapies and overcome resistance mechanisms. This includes combinatorial approaches that integrate immunotherapy, chemotherapy, and targeted therapies to simultaneously address both tumor cells and their supportive microenvironment (Kumari et al. 2021) [3].

In conclusion, the TME is a pivotal factor in cancer progression and treatment resistance. Its components not only support tumor growth and survival but also facilitate mechanisms that lead to therapeutic resistance. Targeting the TME represents a promising avenue for enhancing cancer treatment efficacy and improving patient outcomes. Understanding the complex interactions within the TME will be essential for the development of more effective cancer therapies.

5 Therapeutic Implications of Targeting the TME ​

5.1 Current Strategies in Clinical Trials ​

The tumor microenvironment (TME) plays a crucial role in cancer progression by creating a supportive niche that facilitates tumor initiation, growth, and metastasis. It consists of various cellular components, including fibroblasts, immune cells, endothelial cells, and the extracellular matrix, all of which interact dynamically with cancer cells. These interactions significantly influence tumor behavior and therapeutic responses, making the TME a promising target for cancer therapies.

The TME contributes to cancer progression through several mechanisms. It influences tumor cell growth, migration, and invasion by providing essential signals and structural support. For instance, the activation of pathways such as epithelial-mesenchymal transition (EMT) allows tumor cells to gain migratory and invasive capabilities, enhancing their metastatic potential [5]. Moreover, the TME is known to foster an immunosuppressive environment, which can lead to therapy resistance and cancer recurrence [47]. Understanding these complex interactions is vital for developing effective therapeutic strategies.

Therapeutic implications of targeting the TME have gained considerable attention in recent years. By disrupting the supportive interactions between cancer cells and their microenvironment, it may be possible to enhance the efficacy of existing treatments and overcome resistance. For example, combination therapies that include chemotherapy, immunotherapy, and agents specifically targeting TME components are being explored [3]. The goal is to not only target cancer cells directly but also to modify the TME to make it less conducive to tumor growth and survival [48].

Current strategies in clinical trials reflect this shift towards targeting the TME. Numerous studies are underway to assess the effectiveness of therapies that aim to alter the cellular and molecular composition of the TME. These strategies include using agents that inhibit the signaling pathways involved in TME-mediated drug resistance, as well as therapies that enhance immune responses against tumors by modifying the TME [49]. For instance, targeting cancer-associated fibroblasts and macrophages, which play significant roles in creating a supportive environment for tumors, is being investigated as a means to improve treatment outcomes [29].

In summary, the tumor microenvironment is integral to cancer progression and presents a multifaceted target for therapeutic intervention. By understanding its complex dynamics and developing strategies to disrupt its supportive roles, there is potential for significant advancements in cancer treatment outcomes. Current clinical trials are actively exploring these strategies, aiming to refine and enhance therapeutic efficacy against various malignancies.

5.2 Future Directions for Research ​

The tumor microenvironment (TME) plays a crucial role in cancer progression, influencing various aspects of tumor biology including initiation, growth, metastasis, and response to therapies. The TME is a complex and dynamic network comprising tumor cells, stromal cells, immune cells, and extracellular matrix components. This environment not only supports tumor cell proliferation but also creates a conducive niche for tumor progression and metastasis.

The TME contributes to cancer progression through multiple mechanisms. It is involved in the initiation and promotion of carcinogenesis by providing necessary growth factors and creating a supportive environment for tumor cells. For instance, components such as fibroblasts, endothelial cells, and immune cells interact with cancer cells to facilitate processes like epithelial-mesenchymal transition (EMT), angiogenesis, and immune evasion, all of which are critical for tumor growth and dissemination [5].

Targeting the TME has emerged as a promising therapeutic strategy. The interaction between tumor cells and their microenvironment can lead to therapeutic resistance, highlighting the need for approaches that address both tumor cells and their surrounding stroma. Combination therapies that include chemotherapy, immunotherapy, and agents targeting specific components of the TME are being explored to enhance treatment efficacy. For example, therapies that disrupt the immunosuppressive microenvironment or inhibit the pro-tumorigenic signals from stromal cells can potentially improve clinical outcomes [48].

Future research directions should focus on deepening our understanding of the TME's composition and its dynamic interactions with tumor cells. This includes identifying specific molecular targets within the TME that can be exploited for therapeutic benefit. Additionally, the development of novel technologies and models that accurately replicate the TME will be essential for testing new therapeutic strategies. Computational tools can also aid in monitoring the effectiveness of therapies targeting the TME [49].

In summary, the TME is integral to cancer progression and presents a valuable target for therapeutic intervention. Continued research into the mechanisms of TME interactions and the development of combinatorial therapies may lead to more effective cancer treatments and improved patient outcomes.

5.3 Challenges in Targeting the TME ​

The tumor microenvironment (TME) plays a critical role in cancer progression by providing a supportive niche for tumor cells, influencing their behavior, and contributing to therapeutic resistance. The TME consists of various non-cancerous cells, including fibroblasts, immune cells, endothelial cells, and components of the extracellular matrix, which interact dynamically with cancer cells to regulate processes such as tumor initiation, growth, metastasis, and response to therapies.

In terms of cancer progression, the TME is integral in several ways. It facilitates tumor cell proliferation and survival by providing essential growth factors and a supportive extracellular matrix. Furthermore, the TME contributes to the phenomenon of epithelial-mesenchymal transition (EMT), which enhances the migratory and invasive capabilities of cancer cells, thereby promoting metastasis [5]. Additionally, the TME can induce a state of immune suppression, allowing tumor cells to evade immune detection and destruction, further exacerbating cancer progression [47].

Therapeutically, targeting the TME has emerged as a promising strategy to enhance cancer treatment efficacy. By addressing both tumor cells and the supportive cellular components of the TME, combination therapies can improve clinical outcomes compared to traditional therapies that target cancer cells alone [3]. This approach may involve utilizing agents that disrupt the interactions between tumor cells and the TME, thereby mitigating drug resistance and enhancing the effectiveness of immunotherapies [48].

However, several challenges persist in targeting the TME effectively. The complexity and heterogeneity of the TME pose significant hurdles, as different tumors may exhibit distinct microenvironmental characteristics that influence treatment responses [29]. Additionally, the TME can exhibit plasticity, adapting to therapeutic interventions and contributing to treatment resistance [49]. Furthermore, the similarity between tumor-associated stroma and normal tissue complicates the development of selective therapies that do not harm healthy cells [17].

In summary, the tumor microenvironment plays a multifaceted role in cancer progression, offering therapeutic targets that can be exploited to improve treatment outcomes. Nonetheless, the challenges associated with its complexity and adaptability necessitate continued research and innovation to develop effective strategies for targeting the TME in cancer therapy.

6 Conclusion ​

The tumor microenvironment (TME) is a critical determinant of cancer progression, influencing tumor growth, metastasis, and treatment resistance through its complex interactions with cancer cells and various non-cancerous components. Key findings indicate that cancer-associated fibroblasts (CAFs), immune cell infiltration, endothelial cells, and the extracellular matrix (ECM) collectively shape the TME, facilitating a supportive niche for tumor development. Current research emphasizes the need for a comprehensive understanding of these interactions to develop effective therapeutic strategies that target both tumor cells and their microenvironment. Despite the promising potential of TME-targeted therapies, challenges such as the heterogeneity and plasticity of the TME, along with the risk of off-target effects, remain significant hurdles. Future research should focus on elucidating the specific roles of TME components in different cancer types, exploring innovative therapeutic approaches, and developing precise targeting strategies to enhance treatment efficacy and overcome resistance. By addressing these challenges, there is hope for improving patient outcomes and advancing cancer treatment methodologies.

References ​

  • [1] Yao Yuan;Yu-Chen Jiang;Chong-Kui Sun;Qian-Ming Chen. Role of the tumor microenvironment in tumor progression and the clinical applications (Review).. Oncology reports(IF=3.9). 2016. PMID:26986034. DOI: 10.3892/or.2016.4660.
  • [2] Edgardo V Ariztia;Catherine J Lee;Radhika Gogoi;David A Fishman. The tumor microenvironment: key to early detection.. Critical reviews in clinical laboratory sciences(IF=5.5). 2006. PMID:17050079. DOI: 10.1080/10408360600778836.
  • [3] Smita Kumari;Dia Advani;Sudhanshu Sharma;Rashmi K Ambasta;Pravir Kumar. Combinatorial therapy in tumor microenvironment: Where do we stand?. Biochimica et biophysica acta. Reviews on cancer(IF=8.3). 2021. PMID:34224836. DOI: 10.1016/j.bbcan.2021.188585.
  • [4] Eliza Turlej;Aleksandra Domaradzka;Justyna Radzka;Dominika Drulis-Fajdasz;Julita Kulbacka;Agnieszka Gizak. Cross-Talk Between Cancer and Its Cellular Environment-A Role in Cancer Progression.. Cells(IF=5.2). 2025. PMID:40136652. DOI: 10.3390/cells14060403.
  • [5] Feng Gao;Bin Liang;Srinivasa T Reddy;Robin Farias-Eisner;Xiulan Su. Role of inflammation-associated microenvironment in tumorigenesis and metastasis.. Current cancer drug targets(IF=3.5). 2014. PMID:24200082. DOI: 10.2174/15680096113136660107.
  • [6] Bashar Emon;Jessica Bauer;Yasna Jain;Barbara Jung;Taher Saif. Biophysics of Tumor Microenvironment and Cancer Metastasis - A Mini Review.. Computational and structural biotechnology journal(IF=4.1). 2018. PMID:30128085. DOI: 10.1016/j.csbj.2018.07.003.
  • [7] Kim H T Paraiso;Keiran S M Smalley. Fibroblast-mediated drug resistance in cancer.. Biochemical pharmacology(IF=5.6). 2013. PMID:23376122. DOI: .
  • [8] Luís Henrique Corrêa;Rafael Corrêa;Cecília Menezes Farinasso;Lívia Pimentel de Sant'Ana Dourado;Kelly Grace Magalhães. Adipocytes and Macrophages Interplay in the Orchestration of Tumor Microenvironment: New Implications in Cancer Progression.. Frontiers in immunology(IF=5.9). 2017. PMID:28970834. DOI: 10.3389/fimmu.2017.01129.
  • [9] James Mason;Daniel Öhlund. Key aspects for conception and construction of co-culture models of tumor-stroma interactions.. Frontiers in bioengineering and biotechnology(IF=4.8). 2023. PMID:37091337. DOI: 10.3389/fbioe.2023.1150764.
  • [10] Kévin Louault;Rong-Rong Li;Yves A DeClerck. Cancer-Associated Fibroblasts: Understanding Their Heterogeneity.. Cancers(IF=4.4). 2020. PMID:33114328. DOI: 10.3390/cancers12113108.
  • [11] Rachel J Buchsbaum;Sun Young Oh. Breast Cancer-Associated Fibroblasts: Where We Are and Where We Need to Go.. Cancers(IF=4.4). 2016. PMID:26828520. DOI: .
  • [12] Ece Ozmen;Tevriz Dilan Demir;Gulnihal Ozcan. Cancer-associated fibroblasts: protagonists of the tumor microenvironment in gastric cancer.. Frontiers in molecular biosciences(IF=4.0). 2024. PMID:38562556. DOI: 10.3389/fmolb.2024.1340124.
  • [13] Zhanhuai Wang;Yinuo Tan;Wei Yu;Shu Zheng;Suzhan Zhang;Lifeng Sun;Kefeng Ding. Small role with big impact: miRNAs as communicators in the cross-talk between cancer-associated fibroblasts and cancer cells.. International journal of biological sciences(IF=10.0). 2017. PMID:28367098. DOI: 10.7150/ijbs.17680.
  • [14] Zhongnan Yin;Chunxiao Li;Junjie Wang;Lixiang Xue. Myeloid-derived suppressor cells: Roles in the tumor microenvironment and tumor radiotherapy.. International journal of cancer(IF=4.7). 2019. PMID:29992569. DOI: 10.1002/ijc.31744.
  • [15] Javier Mora;Christina Mertens;Julia K Meier;Dominik C Fuhrmann;Bernhard Brüne;Michaela Jung. Strategies to Interfere with Tumor Metabolism through the Interplay of Innate and Adaptive Immunity.. Cells(IF=5.2). 2019. PMID:31083487. DOI: 10.3390/cells8050445.
  • [16] Roy M Bremnes;Lill-Tove Busund;Thomas L Kilvær;Sigve Andersen;Elin Richardsen;Erna Elise Paulsen;Sigurd Hald;Mehrdad Rakaee Khanehkenari;Wendy A Cooper;Steven C Kao;Tom Dønnem. The Role of Tumor-Infiltrating Lymphocytes in Development, Progression, and Prognosis of Non-Small Cell Lung Cancer.. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer(IF=20.8). 2016. PMID:26845192. DOI: .
  • [17] Nor Eddine Sounni;Agnès Noel. Targeting the tumor microenvironment for cancer therapy.. Clinical chemistry(IF=6.3). 2013. PMID:23193058. DOI: 10.1373/clinchem.2012.185363.
  • [18] Ashleigh Unsworth;Robin Anderson;Kara Britt. Stromal fibroblasts and the immune microenvironment: partners in mammary gland biology and pathology?. Journal of mammary gland biology and neoplasia(IF=3.6). 2014. PMID:24984900. DOI: 10.1007/s10911-014-9326-8.
  • [19] Guillaume Collet;Klaudia Skrzypek;Catherine Grillon;Agata Matejuk;Bouchra El Hafni-Rahbi;Nathalie Lamerant-Fayel;Claudine Kieda. Hypoxia control to normalize pathologic angiogenesis: potential role for endothelial precursor cells and miRNAs regulation.. Vascular pharmacology(IF=3.5). 2012. PMID:22446152. DOI: 10.1016/j.vph.2012.03.001.
  • [20] Shiyu Ji;Wenbo Wu;Qi Jiang. Crosstalk between Endothelial Cells and Tumor Cells: A New Era in Prostate Cancer Progression.. International journal of molecular sciences(IF=4.9). 2023. PMID:38069225. DOI: 10.3390/ijms242316893.
  • [21] Tetsuro Watabe;Kazuki Takahashi;Kristian Pietras;Yasuhiro Yoshimatsu. Roles of TGF-β signals in tumor microenvironment via regulation of the formation and plasticity of vascular system.. Seminars in cancer biology(IF=15.7). 2023. PMID:37068553. DOI: 10.1016/j.semcancer.2023.04.007.
  • [22] Hyojeong Choi;Aree Moon. Crosstalk between cancer cells and endothelial cells: implications for tumor progression and intervention.. Archives of pharmacal research(IF=7.5). 2018. PMID:29961196. DOI: 10.1007/s12272-018-1051-1.
  • [23] Victor Oginga Oria;Janine Terra Erler. Tumor Angiocrine Signaling: Novel Targeting Opportunity in Cancer.. Cells(IF=5.2). 2023. PMID:37887354. DOI: 10.3390/cells12202510.
  • [24] Meiling Zhang;Bin Zhang. Extracellular matrix stiffness: mechanisms in tumor progression and therapeutic potential in cancer.. Experimental hematology & oncology(IF=13.5). 2025. PMID:40211368. DOI: 10.1186/s40164-025-00647-2.
  • [25] Evelina Poletto;Naike Casagrande;Emanuele Di Siena;Greta Carobolante;Lucrezia Camicia;Giorgia Schinello;Samanta Muzzin;Enrica Timis;Paola Spessotto;Maurizio Mongiat. Behind the scenes: how the EMILIN/Multimerin family shapes the cancer landscape.. The FEBS journal(IF=4.2). 2025. PMID:41194556. DOI: 10.1111/febs.70306.
  • [26] Valentina Poltavets;Marina Kochetkova;Stuart M Pitson;Michael S Samuel. The Role of the Extracellular Matrix and Its Molecular and Cellular Regulators in Cancer Cell Plasticity.. Frontiers in oncology(IF=3.3). 2018. PMID:30356678. DOI: 10.3389/fonc.2018.00431.
  • [27] Nadezhda V Popova;Manfred Jücker. The Functional Role of Extracellular Matrix Proteins in Cancer.. Cancers(IF=4.4). 2022. PMID:35008401. DOI: 10.3390/cancers14010238.
  • [28] Alexandra M Socovich;Alexandra Naba. The cancer matrisome: From comprehensive characterization to biomarker discovery.. Seminars in cell & developmental biology(IF=6.0). 2019. PMID:29964200. DOI: 10.1016/j.semcdb.2018.06.005.
  • [29] Magdalena Dutsch-Wicherek;Wojciech Kazmierczak. Creation of a suppressive microenvironment by macrophages and cancer-associated fibroblasts.. Frontiers in bioscience (Landmark edition)(IF=3.1). 2013. PMID:23747863. DOI: 10.2741/4159.
  • [30] Marta Giussani;Tiziana Triulzi;Gabriella Sozzi;Elda Tagliabue. Tumor Extracellular Matrix Remodeling: New Perspectives as a Circulating Tool in the Diagnosis and Prognosis of Solid Tumors.. Cells(IF=5.2). 2019. PMID:30678058. DOI: 10.3390/cells8020081.
  • [31] Romi Gupta. Epigenetic regulation and targeting of ECM for cancer therapy.. American journal of physiology. Cell physiology(IF=4.7). 2022. PMID:35235427. DOI: 10.1152/ajpcell.00022.2022.
  • [32] Srijan Dubey;Sayak Ghosh;Debosmita Goswami;Debapriya Ghatak;Rudranil De. Immunometabolic attributes and mitochondria-associated signaling of Tumor-Associated Macrophages in tumor microenvironment modulate cancer progression.. Biochemical pharmacology(IF=5.6). 2023. PMID:36481347. DOI: 10.1016/j.bcp.2022.115369.
  • [33] Simon P Daoust;Lenore Fahrig;Amanda E Martin;Frédéric Thomas. From forest and agro-ecosystems to the microecosystems of the human body: what can landscape ecology tell us about tumor growth, metastasis, and treatment options?. Evolutionary applications(IF=3.2). 2013. PMID:23396712. DOI: 10.1111/eva.12031.
  • [34] Sun-Ah Lee;Gi-Ju Cho;Doyoung Kim;Dong-Hwee Kim. Biophysical interplay between extracellular matrix remodeling and hypoxia signaling in regulating cancer metastasis.. Frontiers in cell and developmental biology(IF=4.3). 2024. PMID:38544822. DOI: 10.3389/fcell.2024.1335636.
  • [35] Sara Hadjigol;Bansari A Shah;Neil M O'Brien-Simpson. The 'Danse Macabre'-Neutrophils the Interactive Partner Affecting Oral Cancer Outcomes.. Frontiers in immunology(IF=5.9). 2022. PMID:35784290. DOI: 10.3389/fimmu.2022.894021.
  • [36] Dolores Aguilar-Cazares;Rodolfo Chavez-Dominguez;Mario Marroquin-Muciño;Mario Perez-Medina;Jesus J Benito-Lopez;Angel Camarena;Uriel Rumbo-Nava;Jose S Lopez-Gonzalez. The systemic-level repercussions of cancer-associated inflammation mediators produced in the tumor microenvironment.. Frontiers in endocrinology(IF=4.6). 2022. PMID:36072935. DOI: 10.3389/fendo.2022.929572.
  • [37] Albashir Alzawi;Anem Iftikhar;Basher Shalgm;Sarah Jones;Ian Ellis;Mohammad Islam. Receptor, Signal, Nucleus, Action: Signals That Pass through Akt on the Road to Head and Neck Cancer Cell Migration.. Cancers(IF=4.4). 2022. PMID:35681586. DOI: 10.3390/cancers14112606.
  • [38] María Belén Novoa Díaz;María Julia Martín;Claudia Gentili. Tumor microenvironment involvement in colorectal cancer progression via Wnt/β-catenin pathway: Providing understanding of the complex mechanisms of chemoresistance.. World journal of gastroenterology(IF=5.4). 2022. PMID:36051330. DOI: 10.3748/wjg.v28.i26.3027.
  • [39] Adrian C Shieh. Biomechanical forces shape the tumor microenvironment.. Annals of biomedical engineering(IF=5.4). 2011. PMID:21253819. DOI: 10.1007/s10439-011-0252-2.
  • [40] Christine M Gould;Sara A Courtneidge. Regulation of invadopodia by the tumor microenvironment.. Cell adhesion & migration(IF=3.5). 2014. PMID:24714597. DOI: 10.4161/cam.28346.
  • [41] Alec C Kimmelman;Mara H Sherman. The Role of Stroma in Cancer Metabolism.. Cold Spring Harbor perspectives in medicine(IF=10.1). 2024. PMID:37696660. DOI: 10.1101/cshperspect.a041540.
  • [42] Ziheng Zhang;Yajun Hu;Yuefeng Chen;Zhuoneng Chen;Yexin Zhu;Mingmin Chen;Jichu Xia;Yixuan Sun;Wenfang Xu. Immunometabolism in the tumor microenvironment and its related research progress.. Frontiers in oncology(IF=3.3). 2022. PMID:36387147. DOI: 10.3389/fonc.2022.1024789.
  • [43] Yadi Wu;Binhua P Zhou. Inflammation: a driving force speeds cancer metastasis.. Cell cycle (Georgetown, Tex.)(IF=3.4). 2009. PMID:19770594. DOI: 10.4161/cc.8.20.9699.
  • [44] Daniela F Quail;Morag Park;Alana L Welm;H Atakan Ekiz. Breast Cancer Immunity: It is TIME for the Next Chapter.. Cold Spring Harbor perspectives in medicine(IF=10.1). 2024. PMID:37188526. DOI: 10.1101/cshperspect.a041324.
  • [45] Naji Kharouf;Thomas W Flanagan;Sofie-Yasmin Hassan;Hosam Shalaby;Marla Khabaz;Sarah-Lilly Hassan;Mosaad Megahed;Youssef Haikel;Simeon Santourlidis;Mohamed Hassan. Tumor Microenvironment as a Therapeutic Target in Melanoma Treatment.. Cancers(IF=4.4). 2023. PMID:37370757. DOI: 10.3390/cancers15123147.
  • [46] Dhruba Kadel;Yu Zhang;Hao-Ran Sun;Yue Zhao;Qiong-Zhu Dong;Lun-Xiu Qin. Current perspectives of cancer-associated fibroblast in therapeutic resistance: potential mechanism and future strategy.. Cell biology and toxicology(IF=5.9). 2019. PMID:30680600. DOI: 10.1007/s10565-019-09461-z.
  • [47] Irene Di Ceglie;Silvia Carnevale;Anna Rigatelli;Giovanna Grieco;Piera Molisso;Sebastien Jaillon. Immune cell networking in solid tumors: focus on macrophages and neutrophils.. Frontiers in immunology(IF=5.9). 2024. PMID:38426089. DOI: 10.3389/fimmu.2024.1341390.
  • [48] Yi Xiao;Dihua Yu. Tumor microenvironment as a therapeutic target in cancer.. Pharmacology & therapeutics(IF=12.5). 2021. PMID:33259885. DOI: 10.1016/j.pharmthera.2020.107753.
  • [49] Emma H Allott;Kellie Dean;Tracy Robson;Claire Meaney. Characterizing and Exploiting Tumor Microenvironments to Optimize Treatment Outcomes.. Cancers(IF=4.4). 2021. PMID:34830906. DOI: 10.3390/cancers13225752.

MaltSci Intelligent Research Services ​

Search for more papers on MaltSci.com ​

tumor microenvironment · cancer progression · cancer-associated fibroblasts · immune cell infiltration · angiogenesis

© 2025 MaltSci