Abstract
The treatment of various cancers has been transformed through cancer immunotherapy, which has been able to produce lasting and, in some instances, curative responses even in the face of the more traditional therapies of surgery, radiotherapy, and chemotherapy. The incumbent modalities, which are immune checkpoint inhibitors, adoptive cell therapies, cancer vaccines, cytokine-based platforms, and oncolytic viruses, have achieved unprecedented clinical efficacy, specifically in melanoma, lung cancer, and hematologic malignancies. Despite these developments, long-term clinical efficacy is only attainable in a small group of patients, with primary and acquired resistance being the most significant obstacles in achieving long-term effectiveness and expansive clinical implementation.
The phenomenon of immunotherapy resistance is a complicated and dynamic interplay of tumor-intrinsic changes, immune evasion strategies, and immunosuppressive tumor microenvironmental conditions, which are also caused by host-related factors, including microbiome composition and genetic diversity. The current and novel predictive biomarkers, including tumor-based, immune-associated, genomic, transcriptomic, and liquid biopsy, are subjectively discussed in their role to narrow patient stratification and precision immunotherapy. Moreover, new treatment approaches that can overcome resistance are also mentioned, such as rational combination regimens, inhibition of new immune checkpoints and costimulatory pathways, metabolic and epigenetic reprogramming, microbiome-based interventions, and neoantigen-based personalized therapies. Together, these observations provide the map for improving the sustainability, efficiency, and individualization of cancer immunotherapy and define immunotherapy resistance as an opportunity to be addressed instead of an unavoidable disadvantage.