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
Year: 2026
Type: article
Abstract: 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.
Source: Bioactive Materials
Institutions: Chinese Academy of Medical Sciences & Peking Union Medical College, Cancer Hospital of Chinese Academy of Medical Sciences, State Key Laboratory of Molecular Oncology, Shandong University, Qilu Hospital of Shandong University, Zhengzhou University, Henan Cancer Hospital, Shanghai University of Engineering Science, Nanjing Medical University
Language: English
Subfield: Biomaterials
Field: Materials Science
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $2,200
OpenAlex ID: W7225792122