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

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.