Enhancing gastric cancer immunotherapy: Insights from multi-omics analysis and innovations in photodynamic-chemotherapy nanoplatforms.

Abstract

Overcoming resistance to immune checkpoint blockade (ICB) therapy in gastric cancer (GC) remains a major clinical challenge. Here, we apply multi-omics profiling, including single-cell RNA sequencing and spatial transcriptomics, to GC tissues from patients receiving neoadjuvant ICB therapy to identify drivers of resistance. We identify tumor-intrinsic Yes-associated protein 1 (YAP1) as a key regulator of immunosuppressive cellular communities that contribute to ICB non-responsiveness. To mitigate the off-target toxicity of verteporfin, a YAP1 inhibitor, we develop macrophage-membrane-camouflaged hollow mesoporous silica nanoparticles (M@O-VNPs) co-loaded with verteporfin and oxaliplatin. This nanoplatform selectively inhibits YAP1, suppresses the CXCL5-CXCR2 axis, and reduces the activity of SPP1⁺ macrophages. By inducing immunogenic cell death, M@O-VNPs remodel the tumor microenvironment and enhance ICB efficacy while minimizing systemic toxicity. The therapeutic potential of this strategy is supported by synergistic antitumor effects of M@O-VNPs combined with anti-PD-1 therapy in genetically engineered and syngeneic GC models.