Pan-cancer biomarkers of immune therapy resistance: mechanisms and clinical translation

Abstract

Immune checkpoint blockade targeting PD-1/PD-L1 has reshaped cancer therapy across multiple tumor types. However, primary and acquired resistance remain major barriers to durable clinical benefit. Increasing evidence indicates that immunotherapy resistance is not driven by isolated molecular alterations, but by coordinated changes involving tumor-intrinsic immune escape, immunosuppressive tumor microenvironments, systemic inflammatory remodeling, and adaptive biomarker evolution under therapeutic pressure. This review focuses on pan-cancer biomarkers of immune therapy resistance from the perspective of mechanisms and clinical translation. First, we summarize targetable biomarker classes that link resistance biology to therapeutic sensitization across cancers, including transcription factors, genomic alterations, immune checkpoint proteins and metabolic regulators. For each class, we highlight representative cancer types in which experimental or clinical evidence supports their role in immunotherapy resistance. Second, we discuss the mechanistic basis of resistance-associated biomarkers, emphasizing antigen presentation defects, impaired interferon signaling, oncogenic pathway activation, T-cell exhaustion, myeloid and stromal immunosuppression, metabolic reprogramming, and dynamic systemic immune remodeling. These mechanisms provide a biological perspective for interpreting biomarkers not only as predictors of treatment response, but also as functional indicators of resistance evolution. By integrating biomarker classification, resistance mechanisms, and therapeutic sensitization strategies, this review aims to provide a new perspective for using pan-cancer resistance biomarkers to guide rational combination immunotherapy and improve precision cancer treatment.