Overcoming resistance to immune checkpoint inhibitors in cancer: translational mechanisms, dynamic biomarkers, clinically actionable combination strategies, and comparative checkpoint biology.

Immune checkpoint inhibitors (ICIs) have reshaped cancer therapy by restoring antitumor immune activity, yet primary and acquired resistance continue to limit durable clinical benefit. This review integrates the major tumor-intrinsic and tumor-extrinsic mechanisms that drive ICI resistance, including defective antigen presentation, impaired interferon signaling, oncogenic and epigenetic immune escape programs, metabolic rewiring, suppressive myeloid and stromal circuits, abnormal vasculature, and progressive T-cell dysfunction. We discuss these mechanisms in the context of the cancer-immunity cycle and tumor immunotypes, emphasizing how immune-desert, immune-excluded, inflamed-but-suppressed, and adaptive-resistance phenotypes may require different therapeutic strategies. Building on this framework, we evaluate clinically actionable combination approaches, including dual-checkpoint blockade, myeloid and stromal remodeling, radiotherapy or targeted agents to increase tumor antigenicity, DNA damage response-directed combinations, anti-angiogenic strategies, and interventions aimed at preserving or restoring T-cell fitness. Practical considerations for sequencing and patient selection are highlighted according to resistance phenotype, prior ICI exposure, disease tempo, biomarker status, and toxicity risk. We further outline a dynamic biomarker approach that moves beyond single baseline assays by integrating longitudinal tissue and blood-based readouts, including circulating tumor DNA, immune-cell states, soluble immune mediators, T-cell receptor dynamics, and reassessment at progression to guide adaptive therapy. Finally, selected non-oncologic and special clinical contexts, including chronic infections, solid organ transplantation, pre-existing autoimmune disease, and neuroinflammatory or neurodegenerative conditions, are discussed as comparative checkpoint-biology models rather than as separate therapeutic indications. These settings illustrate how chronic antigen exposure, immune exhaustion, tolerance disruption, and immune-related toxicity can inform the understanding of adaptive immune resistance in malignancy. Overall, this review provides a translational framework for matching ICI resistance biology with rational combination strategies and evolving biomarker-guided treatment decisions.