The role of exosomal PD-L1 in NSCLC immunotherapy

Therapeutic resistance and immune evasion are hallmark features associated with tumor progression, wherein tumor cells utilize programmed death-ligand 1 (PD-L1) to inhibit cytotoxic T-cell activity via programmed cell death protein 1 (PD-1) engagement. Anti-PD-1 monoclonal antibodies have shown tremendous success in multiple cancers. Despite their limited efficacy in non-small cell lung cancer (NSCLC), a deeper investigation into the mechanism of PD-L1-mediated immune evasion is needed to combat therapeutic resistance. While some clinical benefits for anti-PD-L1 therapy have been observed in NSCLC, factors, such as durability of response and resistance mechanisms remain barriers to its broader use. Recent findings suggest that exosomal PD-L1 may serve as a critical mediator in these resistance mechanisms while simultaneously promoting cancer progression. Therapeutically targeting the process of exosome biogenesis, which is controlled by neutral sphingomyelinase 2 (nSMase2) and the Rab proteins, could yield a novel treatment strategy. Evidence suggests that knocking down these regulatory proteins may enhance cancer therapy, but that remains to be seen in NSCLC. This review presents a comprehensive overview of exosomal PD-L1 in lung cancer, considering its implications in therapeutic resistance and novel treatment strategies, positioning it as a valuable resource for advancing next-generation immunotherapy approaches.