Reinvigorating immunotherapy: harnessing tumor microenvironment modulation for enhanced cancer treatment

Cancer immunotherapy has transformed the treatment of multiple malignancies, yet primary and acquired resistance remain major barriers to attaining durable clinical benefit. Increasing evidence indicates that immunotherapy failure rarely results from a single mechanism but instead emerges from dynamic interactions within the tumor microenvironment (TME). Recent advances in single-cell, spatial multiomics, and longitudinal profiling have revealed the complex organization of TME-mediated resistance, which can be conceptualized within three interconnected suppressive modules: the tumor-cell-intrinsic module, myeloid-suppressive networks, and stromal barriers. The relative dominance of these modules varies across spatial niches, metastatic sites, disease stages, and treatment phases, leading to profound spatiotemporal heterogeneity and dynamic reorganization of dominant resistance axes. In this Review, we propose a spatiotemporal and systems-level framework for understanding TME-mediated immunotherapy resistance. We discuss how the tumor-cell-intrinsic module contributes to immune escape, how myeloid-suppressive networks and stromal barriers sustain and amplify immunosuppression, and how reciprocal crosstalk among these modules generates feed-forward loops that stabilize resistant states. We also review clinical strategies for remodeling the TME to increase the efficacy of immunotherapeutic approaches. Additionally, we discuss the opportunities and challenges associated with TME remodeling, including safety considerations, emerging biomarkers, and rational combination strategies. We propose that future TME-targeted therapies should transition from component-oriented interventions to dynamic and mechanism-matched strategies guided by dominant resistance axes. This approach aims to facilitate the development of more precise and durable cancer immunotherapies.