Dual-targeted NIR-II AIE theranostic nanoparticles disrupt HNRNPC-driven ITGA1+ myCAFs differentiation and immune evasion in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) remains a therapeutic challenge due to its aggressive metabolism-driven progression and immunosuppressive tumor microenvironment (TME). Through proteomic and transcriptomic analyses, we identified HNRNPC as a novel driver of OSCC progression via aberrant glycolysis and TGF-β-mediated differentiation of ITGA1+ myofibroblastic cancer-associated fibroblasts (myCAFs), which directly induce CD8+ T cell exhaustion. Given the lack of strategies that simultaneously target both tumor and stromal compartments, we engineered a theranostic solution: Near-infrared-II (NIR-II) imaging-guided aggregation-induced emission nanoparticles (AIE NPs) dually conjugated with antibodies against HNRNPC and ITGA1 (NPs-H-I). Studies using molecular experiments, single-nucleus sequencing (snRNA-seq), allograft models, and clinical specimens confirmed that HNRNPC-high OSCCs are enriched with ITGA1+ myCAFs and exhausted CD8+ T cells, correlating with poor patient survival. The developed NPs-H-I demonstrated specific accumulation in tumors, enabling precise NIR-II imaging. Upon 808 nm laser irradiation, NPs-H-I elicited potent photodynamic therapy (PDT), selectively eliminating HNRNPC-high tumor cells and ITGA1+ myCAFs, which robustly inhibited tumor growth and restored anti-tumor immunity in murine models. Our work not only delineates the HNRNPC-ITGA1 axis as a novel metabolic-immune checkpoint in OSCC but also establishes a versatile and translatable precision medicine platform capable of disrupting this pathway for effective combination therapy.