Self‐Assembled Carrier‐Free Nanomedicines Potentiate Chemo‐Photothermal Immunotherapy by Overcoming Prostaglandin E2‐Mediated Immunosuppression

ABSTRACT Inflammation plays a pivotal role in fostering an immunosuppressive tumor microenvironment, which diminishes tumor immunogenic cell death (ICD) and subsequently promotes tumor recurrence and metastasis. The COX‐2/PGE2 signaling axis has been identified as a crucial regulator in the establishment of immunosuppressive conditions. Herein, this work developed an excipient‐free nanomedicine (IPC NPs) via non‐covalent self‐assembly, integrating indocyanine green and paclitaxel (dual ICD inducers) with celecoxib (COX‐2/PGE2 inhibitor) for combined chemo‐photothermal therapy with anti‐inflammatory effects. The IPC NPs displayed monodisperse characteristics with optimal near‐infrared responsiveness, significantly enhancing tumor tissue permeation while demonstrating synergistic chemo‐photothermal cytotoxicity against triple‐negative breast cancer (TNBC). Notably, IPC NPs‐encapsulated celecoxib effectively remodeled the tumor inflammatory microenvironment by attenuating therapy‐induced inflammatory responses, thereby potentiating ICD. This triple therapy regimen promoted dendritic cell maturation, enhanced cytotoxic T lymphocyte infiltration into tumor tissues, and upregulated effector memory T cell populations in TNBC. These immunomodulatory effects substantially ameliorated the immunosuppressive tumor microenvironment, leading to significant inhibition of primary tumor growth and metastasis. Collectively, this work presents a novel carrier‐free nanotherapeutic strategy that synergistically combines chemo‐photothermal‐inflammatory suppression therapy, offering a promising approach for TNBC.