Conjugated polymer nanoparticles (CPNs)-based optogenetic platform reprogramming the tumor microenvironment of MSS colorectal cancer

Illustration of the remote control cancer immunotherapy mediated by photothermal conjugated polymer nanoparticles (CPNs) as showed localized, heat-triggered expression of IFN-γ and IL-2 reshape the TME by promoting macrophage repolarization and T cell proliferation. • This study demonstrated that the near-infrared (NIR)-responsive nanoplatform based on conjugated polymer nanoparticles (CPNs) enable localized photothermal gene activation. • By means of heat-triggered plasmid release driving paracrine IFN-γ/IL-2 production in tumors, this platform lead to cytokine-induced macrophage repolarization and T-cell proliferation via JAK-STAT, converting immunologically “cold” MSS tumors into “hot” lesions for immune attack. • Spatially controlled platform reduces systemic toxicity while boosting antitumor immunity. Microsatellite-stable (MSS) tumors, characterized by an immune-desert tumor microenvironment (TME), are notoriously resistant to systemic immunotherapies. Herein, near-infrared (NIR)-responsive nanoplatform based on donor–acceptor structured conjugated polymer nanoparticles (CPNs) coupled with a heat shock protein 70 (HSP70)-driven plasmid co-encoding IFN-γ, IL-2, and EGFP was developed to reprogramme the TME. CPN-mediated photothermal heating induces localized plasmid transcription, enabling paracrine release of IFN-γ and IL-2. These cytokines are predicted to drive macrophage repolarization toward an M1-like phenotype and enhance T cell proliferation via JAK–STAT signaling, thereby converting immunologically “cold” MSS tumors into “hot” lesions amenable to immune attack. This strategy offers a spatially controlled approach to bypass systemic toxicity while potentiating antitumor immunity.