Feedback-Amplified Drug Delivery of αPD-L1-Modified Lipoplatin for Chronological Synergy in NSCLC through PD-L1 Upregulation

The limited efficacy of PD-L1 blockade in non-small cell lung cancer (NSCLC) patients with low PD-L1 expression necessitates the optimization of therapeutic strategies. In this study, we found that PD-L1 expression levels correlate with survival outcomes in αPD-L1-treated NSCLC patients and cisplatin significantly upregulates PD-L1 expression. Building on these findings, PD-L1 antibody-conjugated liposomal cisplatin (αPD-L1@Lipoplatin) is fabricated to integrate chemotherapy-induced PD-L1 upregulation with feedback-enhanced drug delivery and targeted immune checkpoint blockade to enhance NSCLC immunotherapy. Interestingly, the selective targeting ability of αPD-L1@Lipoplatin further upregulates PD-L1 expression, creating a positive feedback loop that continually increases the density of targeting sites and improves drug delivery efficiency. In parallel, αPD-L1@Lipoplatin enhances cytotoxic CD8⁺ T-cell infiltration, suppresses immunosuppressive regulatory T cells, and increases intratumoral levels of interferon-γ (IFN-γ) and granzyme B, contributing to the chronological synergy between chemotherapy and immunotherapy, thereby boosting the αPD-L1 response and NSCLC inhibition. Importantly, αPD-L1@Lipoplatin effectively suppresses tumor growth without causing significant hepatorenal toxicity, maintaining stable body weight and showing no histopathological abnormalities in major organs. This feedback-amplified drug delivery system offers a promising strategy to enhance drug delivery efficiency and αPD-L1 responsiveness, holding great potential for improving NSCLC immunotherapy.