Targeted tumor cell-intrinsic CTRP6 biomimetic codelivery synergistically amplifies ferroptosis and immune activation to boost anti-PD-L1 immunotherapy efficacy in lung cancer

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.