Abstract Immune checkpoint blockade targeting programmed death ligand-1 (PD-L1) has emerged as a cornerstone of cancer immunotherapy, yielding durable responses in subsets of patients across multiple malignancies. However, clinical outcomes remain limited due to incomplete blockade, low tumor immunogenicity, and poor targeting specificity. Here, we report the development of a chondroitin sulfate-modified liposomal formulation (OPCR-Lip) designed to achieve comprehensive PD-L1 blockade while reprogramming the tumor microenvironment to enhance immune activation. OPCR-Lip binds membrane-bound PD-L1, disrupts PD-L1 glycosylation, and inhibits exosomal PD-L1 secretion by damaging the Golgi apparatus, thereby mitigating immunosuppressive signaling. Co-delivery of oxaliplatin (OXA) further promotes immunogenic cell death, enhancing tumor immunogenicity and sustaining anti-tumor immunity in 4T1 breast tumor-bearing mice. The formulation's therapeutic precision was evaluated through circadian rhythm-based dosing, cross-species in vitro validation (canine and human breast cancer cells), and in vivo efficacy across melanoma and lung cancer models. Collectively, this study presents a promising therapeutic platform that augments PD-L1 blockade, broadens its clinical applicability, and improves treatment safety and effectiveness in solid tumors.
Li et al. (Sun,) studied this question.