Senescence Reprogramming Unleashes Tumor Immune Surveillance via Coordinated Gene Modulation

Abstract Cellular senescence can recruit immune cells for tumor therapy through the senescence‐associated secretory phenotype (SASP). However, its therapeutic efficacy is limited by immune tolerance and the immunosuppressive tumor microenvironment (TME). Reprogramming tumor‐specific senescence through coordinated modulation of P16 INK4a and PD‐L1 enhances tumor immunogenicity and alleviates immunosuppression. To achieve this, a target‐enhanced gene delivery nanoparticle is engineered using the urokinase plasminogen activator receptor (uPAR) as a senescence‐specific targeting ligand, combined with a telomerase reverse transcriptase (TERT) promoter and a nuclear localization signal‐microtubule‐associated sequence (NLS‐MTAS) peptide. This system efficiently induces tumor‐specific senescence through cell‐cycle arrest and promotes the chemotactic recruitment of cytotoxic immune cells. In vivo, the nanoparticle induces a robust anti‐tumor response without causing systemic toxicity and significantly enhances the therapeutic efficacy of αCTLA‐4 immune checkpoint blockade in subcutaneous, lung metastasis, postoperative recurrence, and spontaneous tumor models. This study emphasizes the therapeutic potential of reprogramming tumor‐specific senescence to improve targeted gene delivery and immunotherapy outcomes, offering a viable approach for the treatment of immunologically “cold” tumors.