Reprogramming the immunosuppressive microenvironment in MSS/pMMR colorectal cancer via synergistic pyroptosis induction and PD-L1 suppression.

Colorectal cancer (CRC) with microsatellite-stable (MSS)/pMMR status resists immune checkpoint blockade due to its immunologically "cold" tumor microenvironment. We developed Lipo-LPS-Rg3, a dual-functional nanoliposome co-delivering lipopolysaccharide (LPS) and ginsenoside Rg3, to simultaneously ignite pyroptosis and attenuate PD-L1-associated immune suppression. LPS triggered GSDMD-mediated pyroptosis, releasing DAMPs and recruiting CD8+ T cells, while Rg3 reduced PD-L1 expression in vitro, at least partly by inhibiting NFATc1 nuclear translocation. In vivo, Lipo-LPS-Rg3 decreased PD-L1 protein expression in tumor tissues and promoted both CD8+ T-cell infiltration and IFN-γ-producing effector function. The nanoplatform achieved tumor-targeted delivery, induced near-complete regression in colorectal cancer, and exhibited minimal systemic toxicity. By converting "cold" tumors into "hot" and supporting antitumor T-cell activity, Lipo-LPS-Rg3 offers a promising strategy for MSS/pMMR CRC immunotherapy.