Targeting senescence-mediated immune resistance for enhanced tumor immunotherapy

Abstract

Cellular senescence, a stable state of cell cycle arrest triggered by intrinsic and extrinsic stressors, has emerged as a pivotal regulator of tumor immunity and therapeutic resistance. Senescent cells exhibit pronounced temporal heterogeneity in immune modulation. Early-stage senescence enhances antitumor immunity by increasing immunogenicity and promoting the secretion of pro-inflammatory factors. In contrast, persistent senescence drives an immunosuppressive tumor microenvironment by recruiting myeloid-derived suppressor cells, upregulating immune checkpoints, and propagating a senescent niche. This temporal duality underlies the paradoxical role of therapy-induced senescence in both tumor suppression and immune evasion. Recent advances in senotherapy, including senolytics, senomorphics, and strategies targeting senescent stromal and immune compartments, offer promising avenues to therapeutically exploit senescence. Emerging approaches integrating prodrug designs, targeted protein degradation, and advanced drug delivery systems allow precise, context-specific modulation of senescence, minimizing off-target effects while potentiating immunotherapy. Here, we provide a comprehensive overview of tumor senescence hallmarks, its dynamic crosstalk with immunity, and emerging therapeutic strategies, highlighting current challenges and opportunities for harnessing senescence to overcome immune resistance and enhance cancer immunotherapy.