Nanosized Shikonin Disrupts Tumor-Cell Mismatch Repair and Synergizes with Manganese to Sensitize Squamous Carcinoma to Immunotherapy

Head and neck squamous cell carcinoma (HNSCC) frequently develops resistance to immune checkpoint blockade (ICB) therapy, resulting from an immune-excluded microenvironment. Immunogenic cell death (ICD) can increase tumor immunogenicity and further augment immune-cell infiltration by releasing immunogenic molecules. Hence, inducing ICD within tumors might be a promising strategy to restore antitumor immunity and sensitize HNSCC to ICB. Herein, we developed shikonin (SHK)-loaded, CGKRK-modified lipid nanoparticles (C-SNPs) and demonstrated that C-SNPs could enrich in tumor cells and induce necroptosis <i>in vitro</i> and <i>in vivo</i>. Transcriptomic profiling revealed that C-SNPs suppressed tumor-cell mismatch repair, which later activated the cGAS-mediated IFN response and further increased the expression of PD-L1. Combining C-SNPs with an anti-PD-1 antibody increased the infiltration of DCs and CD8⁺ T cells, yet the response was limited. Modifying C-SNPs with Mn²⁺ (C-SMNPs) enhanced the activation of cGAS-STING signaling and further boosted the maturation of DCs and the differentiation of cytotoxic T cells within ICB-treated tumors. Importantly, compared to C-SNPs, the combination of C-SMNPs with ICB resulted in more sustained tumor suppression <i>in vivo</i>. Together, we developed a versatile nanoparticle that delivered SHK and Mn²⁺ which sensitized HNSCC to ICB by disrupting tumor-cell mismatch repair and boosting the cGAS-STING-mediated IFN response. This nanosized ICD inducer-based strategy holds therapeutic potential in synergizing with anti-PD-1 immunotherapy to enhance treatment efficacy in HNSCC.