Pemetrexed–Poly(salicylic acid) Assemblies Reshape Immunosuppressive Tumor Microenvironment for Enhanced Chemo-immunotherapy

Although chemotherapy can elicit antitumor immune response by the induction of immunogenic cell death (ICD), cyclooxygenase-2 (COX-2) and its downstream product prostaglandin E 2 (PGE 2 ), as negative immune regulators, impede the effect of antitumor immunotherapy. Herein, we rationally synthesized the COX-2/PGE 2 -inhibiting poly(salicylic acid) (PSA) and constructed the esterase-responsive pemetrexed-conjugated PSA-PEG-FA prodrug nanoparticles (PEM–PPFs) by a self-assembly strategy, thereby inducing sufficient ICD, boosting the migration and maturation of dendritic cells (DCs), and activating cytotoxic T lymphocytes (CTLs) for enhanced chemo-immunotherapy. Meanwhile PEM–PPFs could reactivate intercellular reactive oxygen species (ROS) signaling to further potentiate tumor suppression, and recognize the overexpressed folate receptors (FRs) on the surface of colorectal cancer cells to reach tumor specific enrichment. Accordingly, this work presents a promising approach for the application of pemetrexed-conjugated poly(salicylic acid) nanomedicines for modulation of immunosuppressive tumor microenvironments, and inspires the design of functional old-drug polymers.