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.