D-peptide-nanodrug conjugates synergize VISTA blockade and innate activation for cancer immunotherapy.

Effective cancer immunotherapy is often hindered by V-domain Ig suppressor of T cell activation (VISTA) signaling and myeloid-derived suppressor cells (MDSCs) within tumor microenvironment (TME). Here, we report D-peptide-nanodrug conjugates that synergize VISTA blockade and innate activation to overcome these constraints. We developed Reorpn7, a proteolytically stable D-peptide VISTA inhibitor with high binding affinity and in vitro serum stability. This inhibitor was co-loaded with a toll-like receptor 7/8 (TLR7/8) agonist (R848) into an matrix metalloproteinase-2 (MMP-2) responsive poly lactic-co-glycolic acid (PLGA) nanoplatform (r7PL-PLGA@R848). Upon enrichment in the TME, MMP-2 responsive cleavage enables the precise release of the VISTA-targeting peptide Reorpn7 and the TLR7/8 agonist R848, thereby achieving synergistic therapeutic effect of VISTA blockade and innate immune activation. In MC38 tumor models, this nanosystem significantly increased intratumoral CD8+ T cell infiltration and achieved robust antitumor efficacy without obvious systemic toxicity. Mechanistically, the platform reshaped the TME from an inhibitory milieu into an immunosupportive one by coordinating checkpoint blockade, myeloid reprogramming, and T cell recruitment. This stimuli-responsive paradigm offers a translatable strategy to overcome immune checkpoint blockade resistance in challenging malignancies.