Tumor microenvironment heterogeneity and immunotherapy resistance: multidimensional modulation strategies for precision breakthroughs

The tumor microenvironment (TME) exhibits pronounced spatial and temporal heterogeneity across cancer types, encompassing differences in cellular composition, stromal architecture, and metabolic niches. Rather than being a singular cause, this heterogeneity interacts with tumor-intrinsic mechanisms such as antigen loss and clonal evolution, as well as host-related factors including age, comorbidities, and microbiome, to shape both primary and acquired resistance to immune checkpoint inhibitors (ICIs). In this review, we firstly synthesized mechanistic insights into TME-driven resistance across cellular, metabolic, and spatial axes. Then according to the multidimensional axes of resistance, we summarized current therapeutic strategies to overcome resistance such as combination immunotherapies, bispecific antibodies, engineered cell therapies, metabolic modulators, and precision delivery systems. At last, we described multimodal stratification approaches for patient selection and monitoring as well as individualized treatment, including single-cell genomics, spatial-omics, circulating tumor DNA, and artificial intelligence (AI)-driven pathology. We conclude by highlighting translational pathways for integrating dynamic TME monitoring into clinical decision-making and trial design to enable precision immunotherapy.