Pemetrexed–Poly(salicylic\nacid) Assemblies\nReshape Immunosuppressive Tumor Microenvironment for Enhanced Chemo-immunotherapy

Abstract

Although chemotherapy can elicit\nantitumor immune response\nby the\ninduction of immunogenic cell death (ICD), cyclooxygenase-2 (COX-2)\nand its downstream product prostaglandin E₂ (PGE₂), as negative immune regulators, impede the effect of antitumor\nimmunotherapy. Herein, we rationally synthesized the COX-2/PGE₂-inhibiting poly(salicylic acid) (PSA) and constructed the\nesterase-responsive pemetrexed-conjugated PSA-PEG-FA prodrug nanoparticles\n(PEM–PPFs) by a self-assembly strategy, thereby inducing sufficient\nICD, boosting the migration and maturation of dendritic cells (DCs),\nand activating cytotoxic T lymphocytes (CTLs) for enhanced chemo-immunotherapy.\nMeanwhile PEM–PPFs could reactivate intercellular reactive\noxygen species (ROS) signaling to further potentiate tumor suppression,\nand recognize the overexpressed folate receptors (FRs) on the surface\nof colorectal cancer cells to reach tumor specific enrichment. Accordingly,\nthis work presents a promising approach for the application of pemetrexed-conjugated\npoly(salicylic acid) nanomedicines for modulation of immunosuppressive\ntumor microenvironments, and inspires the design of functional old-drug\npolymers.