Immunosuppressive cells as barriers to cancer therapy: mechanisms and emerging solutions

Abstract

Tumor microenvironment-resident immunosuppressive cells-comprising myeloid-derived suppressor cells, regulatory T cells, and tumor-associated macrophages-constitute primary obstacles to effective cancer immunotherapy. Advances in single-cell and spatial multi-omics have uncovered their substantial functional heterogeneity, tissue-adaptive reprogramming, and organ-specific architectures distinguishing primary tumors from metastatic lesions. Beyond canonical immune checkpoint pathways, non-canonical regulatory layers--including metabolic-immune crosstalk, epigenetic regulation, microbiome-mediated distant signaling, and therapy-induced adaptive remodeling-further reinforce treatment resistance. Based on these mechanistic insights, systematic synergistic strategies have been developed, such as multi-pathway checkpoint blockade, ADC-immunotherapy combinations, temporally and spatially optimized conventional therapies, and targeted agents that deplete or reprogram suppressive populations. Emerging biomarkers, repurposed pharmaceuticals, and pan-cancer therapeutic principles are refining patient stratification and combination regimens. This review offers a comprehensive framework for understanding and surmounting immunosuppressive barriers in cancer therapy.