Mechanisms of Resistance to Cancer Immunotherapy: A Host–Tumor Interaction Perspective; A Review Article

ABSTRACT Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet a substantial proportion of patients develop primary or acquired resistance. Understanding the mechanisms underlying this resistance is critical for improving therapeutic outcomes. This review comprehensively examines resistance mechanisms to cancer immunotherapy through a host–tumor interaction perspective, integrating tumor‐intrinsic factors, the immunosuppressive microenvironment, and systemic host characteristics. Main Findings Resistance arises from multiple interconnected mechanisms: (1) tumor‐intrinsic defects, including impaired antigen presentation, aberrant oncogenic signaling (MAPK, PI3K/AKT/mTOR, and WNT/β‐catenin pathways), and metabolic reprogramming; (2) tumor‐extrinsic factors, including immunosuppressive immune cells (MDSCs, Tregs, and M2 macrophages), physical barriers, and metabolic competition; and (3) systemic host factors, including gut microbiome composition and HLA polymorphisms. These mechanisms collectively create a formidable barrier to effective antitumor immunity. Conclusions A comprehensive understanding of this multimodal crosstalk is essential for developing effective strategies to overcome resistance. Rational combination therapies targeting multiple nodes within the cancer‐immunity cycle, informed by patient‐specific resistance profiles, represent a promising approach to improve immunotherapy efficacy and expand the population of responders.