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

How does immunotherapy overcome cancer resistance? ​

Abstract ​

Cancer remains a leading cause of morbidity and mortality globally, with immunotherapy emerging as a transformative approach to harness the immune system for combating malignancies. Despite the successes of various immunotherapeutic strategies, including immune checkpoint inhibitors, CAR T-cell therapy, and monoclonal antibodies, a significant challenge persists in the form of cancer resistance, characterized by primary and secondary resistance mechanisms. This review delves into the multifaceted nature of cancer resistance, focusing on the tumor microenvironment (TME) and the genetic and epigenetic factors that contribute to resistance. The TME often creates an immunosuppressive environment that inhibits effective immune responses, while genetic alterations can impair antigen presentation and immune recognition. We discuss the potential of combination therapies to enhance immunotherapy efficacy by targeting both the tumor and the immune system, as well as the identification of predictive biomarkers that can guide personalized treatment approaches. Future directions in immunotherapy research highlight the need for innovative strategies to overcome resistance, including personalized therapies that consider individual tumor characteristics and the dynamic interactions within the TME. By synthesizing current knowledge and ongoing research efforts, this review aims to provide insights into how immunotherapy can overcome cancer resistance, ultimately leading to more effective and individualized treatment strategies for patients.

Outline ​

This report will discuss the following questions.

  • 1 引言
  • 2 Mechanisms of Cancer Resistance
    • 2.1 Tumor Microenvironment and Immune Evasion
    • 2.2 Genetic and Epigenetic Factors Contributing to Resistance
  • 3 Types of Immunotherapy
    • 3.1 Immune Checkpoint Inhibitors
    • 3.2 CAR T-Cell Therapy
    • 3.3 Monoclonal Antibodies
  • 4 Combination Therapies to Enhance Efficacy
    • 4.1 Synergistic Approaches with Chemotherapy
    • 4.2 Targeting Multiple Pathways
  • 5 Biomarkers and Predictive Models
    • 5.1 Identifying Predictive Biomarkers
    • 5.2 Models for Treatment Response Prediction
  • 6 Future Directions in Immunotherapy Research
    • 6.1 Personalized Immunotherapy Approaches
    • 6.2 Innovative Therapeutic Strategies
  • 7 总结

1 Introduction ​

Cancer remains one of the leading causes of morbidity and mortality worldwide, with an estimated 19.3 million new cases and nearly 10 million cancer-related deaths in 2020 alone [1]. The complexity of cancer biology, coupled with the heterogeneity of tumor responses to therapy, presents significant challenges in treatment. Traditional therapeutic modalities such as surgery, chemotherapy, and radiation have made considerable strides, yet they often fall short in achieving durable responses, particularly in advanced stages of the disease. The emergence of immunotherapy has revolutionized cancer treatment paradigms, offering a novel approach that harnesses the power of the immune system to specifically target and eradicate malignant cells [1][2].

Immunotherapy encompasses a diverse array of strategies, including immune checkpoint inhibitors, CAR T-cell therapy, and monoclonal antibodies, all aimed at enhancing the immune response against tumors. Despite the remarkable successes seen with these therapies in certain malignancies, a significant proportion of patients exhibit either primary resistance—failure to respond from the outset—or secondary resistance—relapse following an initial positive response [3][4]. Understanding the mechanisms underlying these resistance phenomena is crucial for improving treatment outcomes and personalizing therapeutic strategies [5][6].

Current research indicates that the mechanisms of cancer resistance to immunotherapy are multifaceted, involving both tumor-intrinsic factors, such as genetic mutations and alterations in the tumor microenvironment, and tumor-extrinsic factors, including immune evasion tactics employed by tumors [4][7]. The tumor microenvironment plays a pivotal role in shaping the immune landscape, often creating a suppressive milieu that impedes effective immune responses [3][8]. Moreover, the identification of predictive biomarkers for treatment response remains a critical area of exploration, as these markers can guide the selection of appropriate therapeutic regimens and improve patient stratification [9][10].

This review aims to provide a comprehensive analysis of how immunotherapy can overcome cancer resistance, focusing on several key areas. We will first explore the mechanisms of cancer resistance, emphasizing the tumor microenvironment and genetic and epigenetic factors contributing to resistance. Next, we will discuss various types of immunotherapy, including immune checkpoint inhibitors, CAR T-cell therapy, and monoclonal antibodies, highlighting their respective roles and limitations in the treatment landscape. Following this, we will examine combination therapies that aim to enhance the efficacy of immunotherapy, detailing synergistic approaches with chemotherapy and the targeting of multiple pathways to circumvent resistance [2][11].

In addition, we will delve into the identification of biomarkers and predictive models that can aid in forecasting treatment responses, thus paving the way for more personalized approaches to cancer therapy. Finally, we will outline future directions in immunotherapy research, including innovative therapeutic strategies that aim to improve the effectiveness of existing treatments and address the challenges posed by tumor heterogeneity and immune evasion [4][12].

By synthesizing current knowledge and ongoing research efforts, this review seeks to illuminate the complex interplay between immunotherapy and cancer resistance, ultimately contributing to the development of more effective and individualized treatment strategies for patients facing this formidable disease.

2 Mechanisms of Cancer Resistance ​

2.1 Tumor Microenvironment and Immune Evasion ​

Immunotherapy represents a transformative approach in cancer treatment, aiming to harness the body's immune system to combat malignancies. However, the efficacy of immunotherapy is often hindered by various resistance mechanisms, particularly those associated with the tumor microenvironment (TME). The TME is a complex and dynamic ecosystem that includes tumor cells, stromal cells, immune cells, and extracellular matrix components, all of which can significantly influence therapeutic outcomes.

One of the primary mechanisms of cancer resistance to immunotherapy is the ability of tumors to create an immunosuppressive microenvironment. This immunosuppression can occur through several pathways, including the accumulation of immunosuppressive cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), which inhibit the activation and function of effector T cells that are crucial for an effective immune response (Kim & Cho, 2022) [13]. Additionally, tumor cells can secrete various cytokines and growth factors that promote this immunosuppressive milieu, further impeding the anti-tumor immune response.

The TME also contributes to immune evasion through physical barriers that restrict the infiltration of immune cells into the tumor. The abnormal vasculature often found in tumors can lead to insufficient blood supply and hypoxia, creating an environment that is hostile to immune cell function and proliferation (Lamplugh & Fan, 2021) [14]. Moreover, tumors can exploit mechanisms such as the loss of major histocompatibility complex (MHC) molecules, which are essential for T cell recognition of tumor antigens, thereby reducing the visibility of tumor cells to the immune system (Friedrich et al., 2019) [15].

Recent advancements in immunotherapy aim to overcome these resistance mechanisms by targeting the TME. Strategies include the use of immune checkpoint inhibitors that block inhibitory signals and enhance T cell activation, as well as therapies that modify the TME to restore its immunogenicity (Bai & Cui, 2022) [16]. Combination therapies that integrate immunotherapy with other modalities, such as targeted therapies or radiation, have shown promise in reprogramming the TME to be more conducive to anti-tumor immunity (Charpentier et al., 2022) [17].

Furthermore, ongoing research is focused on identifying biomarkers that can predict responses to immunotherapy based on the characteristics of the TME. By understanding the intricate interplay between tumor cells and the immune landscape, researchers aim to develop personalized treatment strategies that can enhance the effectiveness of immunotherapies and ultimately improve patient outcomes (Tashireva et al., 2024) [18].

In conclusion, while the tumor microenvironment poses significant challenges to the success of immunotherapy through mechanisms of immune evasion and resistance, innovative strategies aimed at modifying this environment and enhancing immune responses hold great potential for overcoming these barriers and improving therapeutic efficacy in cancer treatment.

2.2 Genetic and Epigenetic Factors Contributing to Resistance ​

Immunotherapy has emerged as a transformative approach in cancer treatment, leveraging the body's immune system to combat malignancies. However, resistance to immunotherapy remains a significant challenge, often driven by a multitude of genetic and epigenetic factors that facilitate tumor evasion of immune responses.

Genetic alterations within tumor cells can lead to intrinsic resistance mechanisms. These include mutations that affect key oncogenic pathways, such as the RAS-MAPK, WNT, and PI3K-AKT-mTOR pathways, which can influence immune cell interactions and promote tumor survival despite immune pressure [19]. Additionally, genetic dysregulation can impair antigen processing and presentation, leading to decreased visibility of tumor cells to the immune system [19].

Epigenetic factors also play a critical role in the development of resistance to immunotherapy. Tumors often utilize epigenetic modifications, such as DNA methylation and histone modifications, to silence genes involved in immune recognition and response [20]. For instance, the expression of immune checkpoint molecules can be modulated by epigenetic changes, which may prevent effective T cell activation [20]. Furthermore, the tumor microenvironment can be shaped by epigenetic mechanisms that promote an immunosuppressive milieu, fostering the recruitment of regulatory T cells and myeloid-derived suppressor cells that inhibit anti-tumor immunity [18].

The interplay between genetic and epigenetic factors is complex. For example, genetic mutations may lead to the activation of epigenetic pathways that further enhance immune evasion [21]. This dynamic relationship necessitates a multifaceted approach to overcoming resistance. Current strategies under investigation include combining immune checkpoint inhibitors with epigenetic therapies, which aim to reverse the immune suppression induced by tumors. Such combinations may restore the expression of tumor-associated antigens and enhance the efficacy of immunotherapeutic agents [22].

Moreover, identifying predictive biomarkers that correlate with response to immunotherapy is crucial for optimizing treatment strategies. Research indicates that understanding the tumor's genetic and epigenetic landscape can inform personalized treatment regimens, potentially improving patient outcomes [18].

In conclusion, overcoming cancer resistance in immunotherapy involves a thorough understanding of the genetic and epigenetic mechanisms that contribute to tumor immune evasion. By targeting these pathways, particularly through combination therapies that include epigenetic modulators, there is potential to enhance the effectiveness of immunotherapy and improve clinical outcomes for patients facing resistant cancers.

3 Types of Immunotherapy ​

3.1 Immune Checkpoint Inhibitors ​

Immunotherapy, particularly immune checkpoint inhibitors (ICIs), represents a transformative approach in cancer treatment by harnessing the body’s immune system to target and eliminate cancer cells. However, a significant challenge remains: many patients either do not respond to ICIs or develop resistance after an initial response. Understanding the mechanisms of resistance and exploring strategies to overcome them is crucial for enhancing the effectiveness of immunotherapy.

Immune checkpoint inhibitors function by blocking inhibitory pathways that suppress T-cell activity, thereby reinvigorating antitumor immune responses. Despite their potential, the efficacy of ICIs is variable across different cancer types, with a substantial proportion of patients exhibiting primary or acquired resistance. For instance, studies have shown that response rates to ICIs can be particularly low in common cancers such as breast and prostate cancer, where many patients do not respond at all, while others may initially respond but subsequently develop resistance [2][3].

The mechanisms of resistance to immunotherapy are multifaceted and can be classified into tumor-intrinsic and tumor-extrinsic factors. Tumor-intrinsic factors include genetic mutations, alterations in antigen presentation, and changes in the tumor microenvironment (TME) that can diminish the effectiveness of T-cell responses. For example, the loss of phosphatase and tensin homolog (PTEN) expression and overactivation of the Wnt/β-catenin pathway are associated with reduced immune responses [6]. Additionally, the TME can create an immunosuppressive environment through various means, such as the secretion of immunosuppressive cytokines and the presence of regulatory T cells that inhibit effector T-cell function [23].

To address these challenges, current research is focused on identifying novel combination strategies that target both the tumor and the immune system. For instance, combining ICIs with other therapeutic modalities—such as chemotherapy, radiation, or targeted therapies—may enhance antitumor efficacy by modulating the TME and improving T-cell infiltration into tumors [24]. Moreover, understanding the cellular and molecular interactions within the TME can lead to the identification of new therapeutic targets that may enhance the efficacy of ICIs [25].

Recent advancements also emphasize the importance of biomarker identification to predict patient responses to ICIs. By characterizing the immune landscape of tumors, clinicians can better select patients who are likely to benefit from specific immunotherapeutic approaches [26]. This personalized approach not only improves treatment outcomes but also minimizes unnecessary exposure to ineffective therapies.

Furthermore, innovative strategies are being explored to counteract resistance mechanisms, such as the use of agents that modulate the immune system's response or enhance T-cell activation. For example, combining ICIs with therapies that target the TME, like those that inhibit angiogenesis or alter metabolic pathways, may provide synergistic effects and restore effective immune responses [9].

In conclusion, while immune checkpoint inhibitors have revolutionized cancer therapy, overcoming resistance remains a significant hurdle. Ongoing research into the mechanisms of resistance and the development of combination strategies aimed at enhancing the immune response are essential for improving the clinical outcomes of cancer patients receiving immunotherapy. The focus on personalized medicine, through biomarker identification and tailored treatment regimens, holds promise for maximizing the benefits of immunotherapy in diverse cancer populations [7][27].

3.2 CAR T-Cell Therapy ​

Immunotherapy has emerged as a transformative approach in cancer treatment, particularly in addressing the challenge of cancer resistance. One of the most notable advancements in this field is chimeric antigen receptor (CAR) T-cell therapy, which has shown significant promise in combating treatment-resistant malignancies. This therapeutic modality involves the genetic modification of a patient's T cells to express CARs that target specific tumor-associated antigens, thereby enhancing the immune system's ability to recognize and eliminate cancer cells.

The mechanisms through which immunotherapy, particularly CAR T-cell therapy, overcomes cancer resistance can be understood through several key strategies and innovations:

  1. Targeting Specific Tumor Antigens: CAR T-cell therapy is designed to target unique antigens present on cancer cells. This specificity minimizes off-target effects and enhances the likelihood of effective tumor elimination. The ability to engineer T cells to express CARs that recognize specific tumor antigens allows for a more tailored and potent immune response against malignancies, including those that have developed resistance to conventional therapies (Kuttiappan et al., 2025) [28].

  2. Overcoming the Tumor Microenvironment: Solid tumors often present a hostile microenvironment characterized by immune suppression, hypoxia, and the presence of regulatory T cells. These factors can inhibit the effectiveness of immune responses, including those mediated by CAR T cells. Recent strategies have focused on modifying the tumor microenvironment to enhance CAR T-cell infiltration and function. This includes the use of combination therapies that integrate CAR T-cell therapy with agents that can disrupt immunosuppressive signals or enhance T-cell activation (Hauth et al., 2021) [29].

  3. Innovative Engineering of CAR T Cells: Advances in genetic engineering, particularly the use of CRISPR-Cas9 technology, have enabled the development of CAR T cells with enhanced persistence and efficacy. By optimizing CAR design and T-cell signaling pathways, researchers aim to improve the in vivo function and durability of CAR T cells, thereby reducing the likelihood of resistance due to T-cell exhaustion or anergy (Adhikary et al., 2024) [30].

  4. Combination Therapies: The integration of CAR T-cell therapy with other treatment modalities, such as checkpoint inhibitors or radiotherapy, has shown promise in enhancing therapeutic efficacy. These combination strategies can synergistically improve T-cell activation and survival, thereby addressing the mechanisms of resistance that may arise during treatment (Chen et al., 2022) [31]. For instance, adding radiotherapy may help to alter the tumor vasculature and enhance CAR T-cell trafficking to tumor sites, overcoming barriers that typically impede effective T-cell infiltration (Hauth et al., 2021) [29].

  5. Addressing Primary and Secondary Resistance: Immunotherapy can tackle both primary resistance (where tumors do not respond to initial treatment) and secondary resistance (where tumors develop resistance over time). By continuously refining CAR T-cell constructs and employing strategies that target multiple pathways involved in tumor survival, researchers are making strides in mitigating these resistance mechanisms (Ruella et al., 2023) [32].

In conclusion, CAR T-cell therapy represents a sophisticated approach to overcoming cancer resistance by leveraging the body's immune system. Through the targeting of specific tumor antigens, innovative engineering of T cells, and the application of combination therapies, immunotherapy is paving the way for more effective treatments against resistant cancers, particularly in the realm of solid tumors where traditional therapies have often fallen short. The ongoing research and development in this field hold the potential to significantly improve patient outcomes and expand the applicability of CAR T-cell therapy across various malignancies.

3.3 Monoclonal Antibodies ​

Immunotherapy has emerged as a revolutionary approach in cancer treatment, particularly through the use of monoclonal antibodies, which play a crucial role in overcoming cancer resistance. Monoclonal antibodies can specifically target tumor cells and modulate the immune system, thereby enhancing anti-tumor responses while minimizing adverse effects.

Monoclonal antibodies operate through several mechanisms that contribute to their effectiveness against cancer. They can directly target and kill tumor cells, activate immune effector mechanisms such as the complement cascade, and induce antibody-dependent cellular cytotoxicity (ADCC). This multifaceted mechanism is vital in eliciting robust anti-tumor responses while reducing the frequency and severity of adverse events associated with traditional therapies [33].

Despite their effectiveness, resistance to monoclonal antibodies can develop, which is a significant challenge in cancer treatment. Various mechanisms of resistance have been identified, including tumor-associated factors and host-related factors. For instance, preclinical models have elucidated that the tumor microenvironment and the heterogeneity of tumor cells can contribute to the ineffectiveness of monoclonal antibodies over time [34]. Innovative strategies are being explored to circumvent these resistance mechanisms. For example, combination immunotherapy, which involves using monoclonal antibodies alongside other therapeutic agents, can enhance the efficacy of treatment by addressing multiple pathways simultaneously [34].

Recent advancements have also highlighted the importance of immune checkpoint inhibitors, which are a subclass of monoclonal antibodies designed to block inhibitory pathways in T cells, thereby enhancing the immune response against tumors. These agents have shown remarkable success in treating various cancers, including melanoma and lung cancer, but they also face challenges related to resistance and the complexity of the tumor microenvironment [35]. Understanding these resistance mechanisms is crucial for improving patient outcomes and developing more effective treatment regimens.

Moreover, the advent of technologies such as single-cell RNA sequencing has enabled researchers to investigate the tumor's response to immunotherapy at a granular level. This technology allows for the identification of transcriptional changes in response to treatment, helping to uncover the mechanisms by which tumors evade immune detection and suggesting potential therapeutic targets [36].

In summary, monoclonal antibodies in immunotherapy work by directly targeting tumor cells and modulating the immune system to overcome resistance. While challenges remain, ongoing research and innovative approaches, such as combination therapies and advanced sequencing technologies, hold promise for enhancing the effectiveness of immunotherapy in overcoming cancer resistance.

4 Combination Therapies to Enhance Efficacy ​

4.1 Synergistic Approaches with Chemotherapy ​

Immunotherapy has revolutionized cancer treatment by harnessing the immune system to combat malignancies. However, resistance to immunotherapy remains a significant challenge, often resulting in limited efficacy for many patients. To address this issue, combining immunotherapy with chemotherapy has emerged as a promising strategy to enhance therapeutic outcomes.

Chemotherapy, traditionally viewed as immunosuppressive, has been shown to induce immunogenic cell death, which releases tumor antigens and damage-associated molecular patterns (DAMPs) that can stimulate immune responses. This process not only promotes the activation of immune cells but also alters the tumor microenvironment, making it more conducive to immune cell infiltration and activity. For instance, certain chemotherapeutic agents can enhance the infiltration of tumor-infiltrating lymphocytes, thereby overcoming some of the resistance mechanisms associated with immunotherapy[37].

Recent studies have elucidated several mechanisms by which the combination of chemotherapy and immunotherapy can synergistically improve anti-tumor responses. For example, chemotherapy can enhance the effectiveness of immune checkpoint inhibitors (ICIs) by modulating the immune landscape, which is crucial for reprogramming the immunosuppressive tumor microenvironment. This is particularly relevant in the context of immune checkpoint blockade therapies, which have shown durable responses in various cancers but often face challenges due to tumor heterogeneity and the presence of immunosuppressive cells[12].

Clinical evidence supports the efficacy of chemoimmunotherapy in various cancer types. Trials such as KEYNOTE-189 and IMpassion130 have demonstrated that combining chemotherapy with ICIs significantly improves overall survival and progression-free survival compared to chemotherapy alone[38]. Moreover, emerging biomarkers, including tumor mutational burden and PD-L1 expression, are being utilized to refine patient selection for these combination therapies, enhancing the likelihood of favorable responses[39].

Despite the promise of these combination strategies, challenges remain. Managing treatment-related toxicities, determining optimal dosing and sequencing, and addressing potential resistance mechanisms are critical areas of ongoing research[40]. Furthermore, understanding the timing and sequencing of chemotherapy and immunotherapy administration is vital for maximizing their synergistic effects[41].

In conclusion, the integration of chemotherapy with immunotherapy presents a multifaceted approach to overcoming cancer resistance. By leveraging the immunogenic properties of chemotherapy and the targeted action of immunotherapies, this combination strategy holds the potential to enhance treatment efficacy, offering hope for improved outcomes in cancer therapy. Ongoing research and clinical trials will continue to elucidate the optimal strategies for these synergistic approaches, ultimately aiming to transform cancer treatment paradigms.

4.2 Targeting Multiple Pathways ​

Immunotherapy has emerged as a transformative approach in cancer treatment, leveraging the body's immune system to combat malignant cells. However, a significant challenge remains in overcoming resistance to these therapies, which can manifest as either primary or acquired resistance. Combination therapies targeting multiple pathways have been identified as a promising strategy to enhance the efficacy of immunotherapy and address these resistance mechanisms.

The underlying rationale for combination therapies is to engage various aspects of the immune response and tumor biology simultaneously. For instance, immune checkpoint inhibitors (ICIs), which have shown considerable success in treating certain cancers, often face limitations due to tumor heterogeneity, immunosuppressive tumor microenvironments, and immunometabolic rewiring. By integrating ICIs with other modalities such as cytokines, vaccines, or targeted therapies, it is possible to create a multifaceted attack on the tumor, thereby improving patient outcomes [12][42][43].

Combination strategies can effectively target distinct resistance pathways. For example, some tumors may exploit alternative signaling pathways to evade immune detection. By combining ICIs with signal transduction inhibitors, such as antiangiogenic therapies, researchers aim to simultaneously inhibit tumor growth and enhance the immune response [3][44]. This dual approach not only targets the tumor directly but also aims to modulate the tumor immune microenvironment to favor immune activation.

Furthermore, the development of biomarker-guided strategies is crucial for personalizing combination therapies. By analyzing tumor mutational burden, immune cell infiltration, and multi-omic profiling, clinicians can tailor treatments to individual patient profiles, thereby increasing the likelihood of a positive response [43][45]. This personalized approach is essential, as it allows for the identification of patients who are more likely to benefit from specific combinations of therapies, reducing the incidence of ineffective treatments.

The use of engineered materials and novel delivery systems is also an area of active research, aimed at enhancing the efficacy of immunotherapy combinations. For instance, combining immunotherapy with advanced delivery systems can improve drug localization and reduce systemic toxicity, further facilitating a more robust immune response against tumors [46].

In summary, combination therapies represent a critical advancement in overcoming cancer resistance to immunotherapy. By targeting multiple pathways and utilizing a multifaceted approach, these strategies hold the potential to significantly improve treatment outcomes for patients with various malignancies. Ongoing research is essential to refine these approaches, identify effective combinations, and develop predictive biomarkers that can guide clinical decision-making.

5 Biomarkers and Predictive Models ​

5.1 Identifying Predictive Biomarkers ​

Immunotherapy has revolutionized cancer treatment by leveraging the immune system to target and eliminate malignant cells. However, the efficacy of immunotherapy is often limited due to the complex mechanisms of cancer resistance, which can be intrinsic or extrinsic to the tumor. Understanding and identifying predictive biomarkers are crucial for overcoming these resistance mechanisms and improving treatment outcomes.

Predictive biomarkers serve as indicators of how well a patient might respond to immunotherapy. They can be derived from tumor characteristics, host factors, or the tumor microenvironment. For instance, the presence of specific genetic mutations or alterations in the tumor, such as high tumor mutational burden (TMB), can enhance the likelihood of a positive response to immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 and CTLA-4 blockers. Studies have shown that tumors with a high TMB are more likely to produce neoantigens, which can be recognized by the immune system, thus facilitating a stronger anti-tumor response [7].

Additionally, the composition of immune cells within the tumor microenvironment (TME) plays a pivotal role in determining treatment efficacy. High levels of infiltrating T cells, particularly CD8+ T cells, are often associated with better responses to immunotherapy [11]. Conversely, the presence of immunosuppressive cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), can contribute to resistance by inhibiting effective anti-tumor immune responses [8].

Recent advancements in biomarker identification have also focused on exploring the roles of various soluble factors and cytokines within the TME. For example, elevated levels of certain cytokines may indicate a more immunosuppressive environment, thus serving as a negative predictive biomarker [11]. The identification of these biomarkers is critical for stratifying patients and personalizing treatment approaches, as not all patients will benefit from the same immunotherapeutic strategies [9].

Furthermore, predictive models that integrate multi-omic data (genomic, transcriptomic, proteomic) can enhance the understanding of tumor-immune interactions and identify patients who are more likely to respond to specific immunotherapies [12]. Such models can also assist in predicting the likelihood of resistance development, enabling the implementation of combination therapies that may mitigate resistance [10].

In conclusion, the identification of predictive biomarkers and the development of robust predictive models are essential for overcoming cancer resistance to immunotherapy. By tailoring treatment based on these biomarkers, clinicians can enhance the efficacy of immunotherapy, ultimately leading to improved clinical outcomes for patients facing various malignancies.

5.2 Models for Treatment Response Prediction ​

Immunotherapy has emerged as a transformative approach in cancer treatment, particularly for malignancies such as non-small cell lung cancer (NSCLC) and others. However, a significant challenge remains in the form of primary and acquired resistance to these therapies. Understanding how immunotherapy can overcome cancer resistance involves exploring various biomarkers and predictive models that inform treatment response.

One of the primary mechanisms of resistance to immunotherapy is the tumor microenvironment (TME), which can exhibit immunosuppressive properties that inhibit effective immune responses. The identification of predictive biomarkers is crucial for stratifying patients who are likely to benefit from immunotherapy. Established biomarkers such as programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) have been widely utilized to predict responses to immune checkpoint inhibitors (ICIs) [47]. PD-L1 expression, in particular, has been shown to correlate with improved outcomes in patients receiving ICIs, while TMB serves as a measure of the number of mutations within the tumor, which can enhance neoantigen presentation and subsequently immune recognition [48].

Emerging biomarkers also include tumor neoantigens, epigenetic signatures, and markers associated with the TME, such as the presence of tumor-infiltrating lymphocytes (TILs) [47]. These factors contribute to the immunogenicity of tumors and can help predict how well a patient might respond to immunotherapy. For instance, a high TIL count is often associated with better prognosis and response to treatment [3].

Moreover, recent studies have indicated the potential of integrating artificial intelligence (AI) and machine learning (ML) techniques to enhance the predictive capabilities of genetic signatures related to treatment responses [48]. By analyzing vast datasets of genomic and clinical information, researchers aim to identify patterns that correlate with successful immunotherapy outcomes. This systems immunology approach seeks to unravel the complex interplay between tumor and immune cells, thereby facilitating the development of more accurate predictive models [49].

Combination therapies are also being explored as a strategy to overcome resistance. By integrating immunotherapy with other modalities, such as chemotherapy or targeted therapies, the overall efficacy may be enhanced, potentially leading to improved patient outcomes [12]. This combinatorial approach is designed to address various aspects of tumor biology and the immune response, thereby mitigating resistance mechanisms.

In summary, the pathway to overcoming cancer resistance through immunotherapy involves a multifaceted approach that includes the identification of predictive biomarkers, the application of advanced modeling techniques, and the exploration of combination therapies. By refining these strategies, it is possible to enhance the efficacy of immunotherapy and tailor treatments to individual patient profiles, ultimately improving survival outcomes in cancer patients.

6 Future Directions in Immunotherapy Research ​

6.1 Personalized Immunotherapy Approaches ​

Immunotherapy has emerged as a pivotal approach in cancer treatment, leveraging the body's immune system to target and eliminate malignant cells. However, the efficacy of immunotherapy is often hampered by cancer resistance mechanisms, which can be broadly classified into tumor-intrinsic and tumor-extrinsic factors. Understanding and overcoming these resistance mechanisms is crucial for enhancing the effectiveness of immunotherapy.

Tumor-intrinsic resistance arises from characteristics inherent to the cancer cells themselves. These may include genetic mutations, alterations in antigen presentation, and changes in the tumor microenvironment that enable cancer cells to evade immune detection. For instance, the loss of major histocompatibility complex (MHC) molecules can prevent the recognition of tumor antigens by T cells, thereby facilitating immune escape (Friedrich et al. 2019). Additionally, intrinsic factors such as mutations that lead to reduced neoantigen generation can significantly diminish the effectiveness of immune responses (Rieth and Subramanian 2018).

Tumor-extrinsic factors involve the interactions between cancer cells and the surrounding immune microenvironment. The presence of immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells, can inhibit the activation and function of effector T cells, thereby contributing to resistance (Said and Ibrahim 2023). Furthermore, the metabolic alterations within the tumor microenvironment, such as increased levels of indoleamine 2,3-dioxygenase (IDO), can further suppress anti-tumor immunity (Das and Das 2025).

To combat these resistance mechanisms, future directions in immunotherapy research are focusing on personalized approaches. This entails tailoring immunotherapy strategies based on the individual patient's tumor characteristics and immune profile. The integration of biomarker-guided strategies, such as assessing tumor mutational burden and immune cell infiltration, can help identify which patients are most likely to benefit from specific immunotherapeutic agents (Kyriakidis et al. 2025). Moreover, combination therapies that synergistically target multiple pathways involved in immune evasion are being explored. For example, combining immune checkpoint inhibitors with other modalities, such as targeted therapies or radiation, may enhance the overall therapeutic response by addressing both intrinsic and extrinsic resistance mechanisms (Zhu et al. 2021).

In addition to combination therapies, innovative strategies such as nanotechnology are being investigated to improve the delivery and efficacy of immunotherapeutic agents. Nanoparticles can facilitate site-specific delivery of immune modulators and enhance the immune response against tumors, thereby overcoming some of the challenges posed by the tumor microenvironment (Kandasamy et al. 2023).

In conclusion, overcoming cancer resistance to immunotherapy requires a multifaceted approach that includes understanding the complex interplay between tumor biology and the immune system. Personalized immunotherapy strategies, informed by comprehensive biomarker analyses and innovative therapeutic combinations, hold promise for improving patient outcomes and expanding the benefits of immunotherapy across diverse cancer types. As research progresses, these strategies will likely evolve, paving the way for more effective and tailored cancer treatments.

6.2 Innovative Therapeutic Strategies ​

Immunotherapy has revolutionized cancer treatment by harnessing the body's immune system to target and eliminate malignant cells. However, resistance to immunotherapy remains a significant challenge, with a substantial percentage of patients failing to respond to treatment or developing resistance over time. Overcoming this resistance is crucial for enhancing the efficacy of immunotherapy and expanding its benefits to a broader patient population.

Innovative therapeutic strategies are being developed to address the multifaceted nature of immunotherapy resistance. These strategies focus on understanding the underlying mechanisms of resistance, which can be categorized into tumor-intrinsic and tumor-extrinsic factors. Tumor-intrinsic factors include genetic mutations, altered expression of immune checkpoint molecules, and changes in tumor antigenicity, while tumor-extrinsic factors involve the tumor microenvironment (TME), including the presence of immunosuppressive cells and soluble factors that inhibit effective immune responses [11].

Next-generation immunotherapies aim to tackle these challenges by targeting multiple layers of immune regulation. This includes the use of co-inhibitory and co-stimulatory checkpoint modulators, bispecific antibodies, and adoptive cell therapies, which have shown promise in enhancing immune responses against tumors [12]. Additionally, the incorporation of nanotechnology in immunotherapy is emerging as a powerful approach. Nanoparticles can facilitate targeted and sustained delivery of therapeutic agents, enhancing the immune response while minimizing adverse effects associated with off-target activation [11].

Combination therapies represent another innovative strategy to overcome resistance. By integrating immunotherapy with other treatment modalities such as chemotherapy, radiation therapy, and targeted therapies, researchers aim to exploit synergistic effects that enhance overall treatment efficacy [10]. For instance, combining immune checkpoint inhibitors with cytokines or cancer vaccines can improve the immune system's ability to recognize and attack tumor cells [9].

Furthermore, biomarker-guided strategies are crucial for personalizing immunotherapy. By identifying specific biomarkers associated with response or resistance, clinicians can tailor treatment plans to individual patients, improving the likelihood of successful outcomes [12]. Research continues to explore the role of the tumor mutational burden, immune cell infiltration, and multi-omic profiling in predicting patient responses to immunotherapy [12].

The future of immunotherapy research lies in a comprehensive understanding of the complex interactions between the immune system and tumors. Continued investigation into the molecular mechanisms of resistance will facilitate the development of novel therapeutic strategies that can effectively overcome these barriers, ultimately leading to more effective and personalized cancer treatments [4]. By integrating advances in immunology, synthetic biology, and systems medicine, next-generation cancer immunotherapy is poised to transition from a promising intervention to a curative paradigm across various malignancies [12].

7 Conclusion ​

The exploration of mechanisms underlying cancer resistance to immunotherapy has unveiled a complex interplay of tumor-intrinsic and tumor-extrinsic factors. Key findings indicate that the tumor microenvironment (TME) plays a crucial role in mediating immune evasion, with immunosuppressive cells and cytokines significantly impairing effective immune responses. Genetic and epigenetic alterations within tumor cells further contribute to resistance, complicating treatment outcomes. Current immunotherapeutic strategies, including immune checkpoint inhibitors, CAR T-cell therapy, and monoclonal antibodies, have shown promise, yet a substantial proportion of patients experience resistance, necessitating innovative approaches. Combination therapies that integrate immunotherapy with chemotherapy, targeted therapies, and novel agents targeting the TME are being actively researched to enhance treatment efficacy. The identification of predictive biomarkers is essential for personalizing treatment regimens, ensuring that patients receive the most effective therapies based on their tumor characteristics. Future directions in immunotherapy research emphasize personalized approaches, innovative therapeutic strategies, and the need for continued investigation into the mechanisms of resistance. By addressing these challenges, the field aims to transform cancer treatment paradigms and improve outcomes for patients with resistant malignancies.

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