Targeted tumor cell-intrinsic CTRP6 biomimetic codelivery synergistically amplifies ferroptosis and immune activation to boost anti-PD-L1 immunotherapy efficacy in lung cancer
Songhua Cai, Jing Huang, Hongjie Fan, Zhilin Sui, Chujian Huang, Youjun Deng, Ran Jia, Lixu Wang, Kai Ma, Xiaotong Guo, Jie He, Baihua Zhang, Zhentao Yu
Abstract
Lung adenocarcinoma (LUAD) is a refractory tumor with high incidence, high mortality, and easy development of drug resistance. Represented by PD-L1, the rise of immunotherapy and multidrug combinations offers a reliable approach to treating LUAD. However, there are still some patients with immunoresistance or insensitivity, and new combination therapies are still needed. In this study, cyclic arginine-glycine-aspartate (cRGD)/erythrocyte membrane (RBCM) double-head nanocarriers were designed. This nanocarrier platform targets CTRP6 in tumors and delivers gemcitabine to block the progression of lung cancer. PD-L1 monoclonal antibodies were used as a codelivery platform to explore the effect of the codelivery platform on immunotherapy. CTRP6 expression was negatively correlated with the prognosis of patients with lung adenocarcinoma. The codelivery platform @RBCM/cRGD-PhLips effectively targeted tumor cells. Co-carrying gemcitabine and targeting CTRP6 expression, it amplified ferroptosis of tumor cells through the NRF2/STAT3 signaling pathway, activated intratumoral immunity, and promoted M1-like macrophage transformation and CD8+ T-cell recruitment. This platform amplified the immune effect of PD-L1 monoclonal antibodies to play an anti-lung cancer role. The synergistic delivery of the targeted tumor cell-intrinsic CTRP6 biomimetic nanocarrier provides a new approach to the combined immunotherapy of lung cancer.