Therapy-induced senescent cancer cells as bidirectional regulators of antitumor immunity and resistance in the tumor microenvironment

Abstract Cancer immunotherapy has markedly improved patient outcomes, particularly when combined with conventional treatments such as chemotherapy, radiotherapy, and targeted therapy. Following these therapies, however, a subset of cancer cells can enter a senescent state, ceasing proliferation while remaining metabolically active and persistent within tissues. Such therapy-induced senescent cancer cells (TISCCs) significantly influence antitumor immune responses. TISCCs can enhance tumor immunogenicity by presenting neoantigens and activating innate immune pathways. Conversely, they can also promote T-cell immune evasion and therapeutic resistance, ultimately leading to an immunosuppressive tumor microenvironment. This dual role of TISCCs represents a critical determinant of immunotherapy efficacy, making their precise modulation a major challenge for optimizing combination treatment strategies. In this review, we comprehensively examine the opposing roles of TISCCs in antitumor immunity and highlight emerging therapeutic approaches that mitigate TISCC-driven immune suppression and improve the overall efficacy of immunotherapy-based combination regimens.