Insights into the Mechanisms of Immune‐Checkpoint Inhibitors Gained from Spatiotemporal Dynamics of the Tumor Microenvironment
Yuanyuan Zhang, Zhihua Liu
Abstract
Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized cancer treatment, yet durable responses are achieved in only a subset of patients. The tumor microenvironment (TME) plays a key role in cancer progression and immune modulation, critically influencing the efficacy of ICIs. Recent advances in single-cell technologies have enabled high-resolution profiling of the TME, particularly tumor-infiltrating immune cells, across diverse cancer types. However, our understanding of how immune cells shape ICI responses and how they are dynamically altered during treatment remains incomplete. In this review, we summarize recent progress in characterizing TME features associated with ICI responsiveness, highlighting key immune cell subsets involved in ICI therapy and emphasizing their phenotypic plasticity and functional adaptability following ICIs. Additionally, we outline the spatial architecture of the TME in terms of its effects on immune cell behavior and interactions, and discuss the critical role of stromal components and the microbiota in modulating the immune landscape and influencing ICI responsiveness. By integrating these insights, we aim to deepen our understanding of the cellular and molecular mechanisms underlying ICI responses, elucidate determinants of therapeutic sensitivity and resistance, and inform the development of more effective immunotherapeutic strategies.