PSMA-targeted nanoparticles delivering ATR and Src/Bcr-Abl inhibitors to stimulate STING and reprogram senescence-associated secretory phenotype for enhancing immunotherapy in prostate cancer

Significant increases in the proportion of senescent cells were observed in prostate cancer following endocrine therapy. Although treatment-induced senescence (TIS) effectively suppresses cancer cell proliferation, the long-term accumulation of the immunosuppressive senescence-associated secretory phenotype (SASP) promotes immune evasion, leading to the failure of immunotherapy. Herein, a liposomal nanoparticle (T-Lipo@Das/Ber) encapsulating the ATR inhibitor Berzosertib and the Src/Bcr-Abl inhibitor Dasatinib was designed, which can target prostate-specific membrane antigen (PSMA). T-Lipo@Das/Ber efficiently enters cells via PSMA-mediated endocytosis. On the one hand, Berzosertib inhibits ATR, increases DNA damage, and induces the release of type I interferons and pro-inflammatory factors via the cGAS-STING pathway, ultimately enhancing tumor immunogenicity. On the other hand, by inhibiting the Src/Bcr-Abl pathway, Dasatinib reprograms the SASP, reducing the secretion of immunosuppressive factors while promoting the exposure of calreticulin (CRT) and the release of high-mobility group box 1 (HMGB1), thereby synergistically recruiting and activating immune cells. With the stimulation of both innate and adaptive immune responses, “immune cold tumor” is transformed into “immune hot tumor”. When combined with αPD-1, it not only effectively inhibits the growth of the primary tumor, but also induces long-term immune memory to prevent tumor recurrence.