Biomimetic nanoimmunotherapy boosts spatiotemporal PANoptosis and reshapes desmoplastic tumor microenvironment.

Abstract

Dendritic cell (DC)-based vaccines for solid tumors face major challenges, including limited tumor-specific antigens and immunosuppressive stroma. Here, we present a therapeutic nanovaccine (UCNP@MOF@MI@FM [UMMF]) composed of a DC/tumor fused cytomembrane-coated UCNP@MOF nanoparticle, co-loaded with a MutT homolog 1 (MTH1) inhibitor and combined with tetrahydrobiopterin (BH4). The fused membrane facilitates dual targeting to tumors and lymph nodes while enabling broad-spectrum tumor antigen presentation. Upon near-infrared (NIR) irradiation, upconversion-triggered reactive oxygen species (ROS) generation and MTH1 inhibition synergistically induce immunogenic PANoptosis, releasing antigens and promoting DCs maturation. Simultaneously, ROS remodels the tumor stroma by depleting collagen and cancer-associated fibroblasts, enhancing T cell infiltration. BH4 counteracts IDO-mediated kynurenine accumulation, reversing immune tolerance and restoring T cell function. This multifunctional platform integrates tumor cell killing, immune priming, and stromal reprogramming, resulting in robust antitumor immunity, reduced relapse, and metastasis suppression. UMMF offers a promising strategy for precision nanoimmunotherapy through controlled PANoptosis and microenvironment modulation.