Enhancing cisplatin therapy for small cell lung cancer via a dual strategy of combining surufatinib and CD47 blockade.

Small cell lung cancer (SCLC) is a highly lethal malignancy with a < 7 % 5-year survival rate. Platinum-based chemotherapy remains the standard treatment; however, its clinical efficacy is limited. There is an urgent need for new therapeutic strategies. In this study, we developed a RGD labeled liposome (CS/RGD-Lipo) encapsulating both cisplatin and surufatinib as a target delivery system against SCLC, aimed at enhancing ferroptosis to improve cisplatin efficacy, inhibiting angiogenesis, and reversing TAM phenotypes to overcome immunosuppression. Additionally, we combined CS/RGD-Lipo with αCD47 to further enhance antitumor activity. In tumor-bearing mice, CS/RGD-Lipo effectively targeted tumor tissues for the delivery of cisplatin and surufatinib. The combination of CS/RGD-Lipo with αCD47 significantly promoted ferroptosis in SCLC, improved anti-angiogenesis, induced the conversion of M2 macrophages to M1 macrophages, and enhanced the M1 macrophages-mediated antitumor immune response, resulting in a marked inhibition of tumor growth in SCLC mouse models. Taken together, this work demonstrates a feasible therapeutic approach to inhibit SCLC by combining cisplatin, surufatinib, and αCD47 to leverage tumor ferroptosis, angiogenesis inhibition and tumor-associated macrophage polarization.