Aug 2026· Oncology Communications· 0 citations· 131 references
TL;DR
This review presents a systematic synthesis of the principal tumor immunotherapy strategies and their corresponding resistance mechanisms, finding that combination therapies and personalized treatment strategies grounded in TME profiling and biomarkers represent critical future directions.
Abstract
This review presents a systematic synthesis of the principal tumor immunotherapy strategies and their corresponding resistance mechanisms. Immunotherapies—including antibody-based therapies, adoptive cell therapies, immune modulators, and novel approaches such as oncolytic viruses and cancer vaccines—work by stimulating or enhancing the patient's immune system to target cancer cells. Nevertheless, they commonly encounter resistance in clinical applications. Resistance mechanisms predominantly stem from tumor-intrinsic factors and tumor microenvironment (TME) factors. To surmount resistance, combination therapies and personalized treatment strategies grounded in TME profiling and biomarkers represent critical future directions.
Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, CTLA-4, and LAG-3 have transformed cancer therapy, but resistance limits durable benefit. This integrative review summarizes primary, adaptive, and acquired resistance driven by tumor-intrinsic defects, suppressive tumor microenvironmental programs, and host-related factors. We discuss mechanism-based strategies to overcome resistance, including combination immunotherapy, antiangiogenic treatment, TGF-β targeting, myeloid reprogramming, epigenetic and metabolic interventions, microbiome modulation, and cellular or vaccine-based approaches. The findings support a precision immuno-oncology framework based on composite biomarkers, longitudinal monitoring, and adaptive treatment selection matched to dominant resistance mechanisms.
Ehsan Lotfi, F. Golab· Cancer Investigation· 0 citations
This review summarizes emerging therapeutic strategies for EOC, their mechanisms of action, and their potential to overcome treatment resistance, and covers molecularly targeted therapies, immunotherapies, metabolic and epigenetic approaches, cellular and gene therapies, targeted drug-delivery systems, and locoregional and physical modalities.
Zofia Pietrasik, Mikołaj Kapała, Joanna Pietrasik et al.· Cancers· 0 citations
Dr. Priya Hays discusses the mechanisms of treatment resistance in cancer, highlighting their significance for developing better treatment strategies and improving outcomes. When it was discovered in the clinic that both classes of therapies – targeted therapies and cancer immunotherapies – met with responders in the clinic and clinical efficacy, drug-related resistance soon emerged. The mechanisms of resistance for each class of therapy are distinguished by differing molecular pathways and tumor heterogeneity. There are two categories of resistance: innate resistance occurs when cancer cells are non responsive to a therapy before treatment begins, while acquired resistance develops after an initial period of sensitivity. Both forms limit the effectiveness of cancer drugs and immunotherapies. Innate resistance is built into cancer biology through pre-existing mechanisms, including genetic instability and immune evasion. When T cells cannot recognize cancer cells due to a lack of antigens or altered antigen presentation machinery, immune detection of tumor cell death is prevented.
Cancer immunotherapy has transformed the treatment landscape across multiple malignancies; however, durable responses remain limited to a subset of patients due to the emergence of intrinsic and acquired resistance. Increasing evidence suggests that therapeutic immune pressure itself acts as a selective force that shapes tumour evolution, driving the outgrowth of resistant clones. In this review, we synthesise current understanding of the molecular and cellular mechanisms underlying resistance to major immunotherapeutic modalities, including immune checkpoint inhibitors, adoptive cell therapies, and cancer vaccines. We discuss tumour-intrinsic alterations such as defects in antigen presentation and immune signalling pathways, alongside tumour-extrinsic factors including immunosuppressive cell populations, metabolic constraints, and microbiome-mediated modulation. We further examine how these mechanisms converge within the tumour microenvironment to limit therapeutic efficacy. Emerging strategies to overcome resistance are highlighted, including rational combination therapies, next-generation engineered cellular platforms, and precision-guided approaches enabled by multi-omics profiling and artificial intelligence. Collectively, we propose that resistance should be understood as an adaptive consequence of therapeutic immune pressure. Building upon the principles of cancer immunoediting, we discuss how precision immune engineering, the rational design of personalised immunotherapeutic strategies informed by tumour biology, immune context, and predictive biomarkers, may be used to anticipate and overcome evolutionary escape mechanisms.
M. Anwer· International Immunopharmaco...· 0 citations
This review explains how cancer cells bypass standard therapies and highlights next-generation immune targets currently being developed to overcome resistance, and examines how combining new immune-boosting drugs with traditional treatments like chemotherapy, radiation, and novel targeted therapies can weaken cancer defenses.
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced malignancies; however, their efficacy in solid tumors remains limited by therapy resistance. This resistance arises from the metabolic reprogramming of immune cells in the tumor microenvironment (TME), a metabolic 'cage' where immune and cancer cells compete for nutrients. Immune effector cells succumb to metabolic exhaustion amid nutrient competition, whereas immunosuppressive cells augment inhibitory functions via metabolic adaptation, collectively mediating tumor immune evasion. This review systematically delineates the metabolic reprogramming features of immune cells in the TME, dissects the molecular mechanisms governing ICI resistance, and summarizes combination strategies targeting metabolic pathways to reverse resistance, providing theoretical and translational insights for optimizing cancer immunotherapy.
Zhi Xu, Kequan Xu, Yi Ju et al.· Trends in Cancer· 0 citations
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