Abstract

Triple-negative breast cancer (TNBC) is constrained by an immunologically “cold” tumor microenvironment (TME), limiting the benefits of immune checkpoint blockade. Here we develop a safe, orally delivered nanotherapeutic platform based on exosome-like nanoparticles derived from Tetrastigma hemsleyanum Diels et Gilg (TNPs). Owing to their biogenic vesicular architecture, TNPs exhibit excellent gastrointestinal stability, biocompatibility, and preferential uptake by intestinal antigen-presenting cells, thereby overcoming key barriers of oral delivery. Oral TNPs induce Th1-skewed immune activation and remodel gut microbiota, which collectively drive systemic immune reprogramming. In TNBC, these gut-initiated responses increase CD8 + and IFN- γ + T-cell infiltration, favor M1-like macrophage polarization, and reduce regulatory T cells, converting “cold” tumors into an immune-inflamed phenotype. Mechanistically, TNPs attenuate IFN- γ -induced PD-L1 upregulation via STAT1 suppression, mitigating adaptive immune resistance. Consequently, TNPs synergize with anti-PD-L1 therapy to enhance tumor regression without additional toxicity. This work establishes a natural exosome-inspired oral nanoplatform that couples drug-delivery advantages with potent immunomodulation through the gut–tumor immune axis, highlighting its translational potential for sensitizing refractory cancers to immune checkpoint blockade.