NLRX1 contributes to immunotherapeutic resistance of head and neck squamous cell carcinoma by suppressing type I interferon pathway.

BACKGROUND

Head and neck squamous cell carcinoma (HNSCC) faces challenges with limited immune checkpoint inhibitors (ICIs) efficacy. This study identifies NLRX1, highly expressed in HNSCC tumor cells, as a key driver of immune evasion and ICIs' resistance.

METHODS

This study investigated the role of NLRX1 in HNSCC immune evasion and ICIs resistance. We performed retrospective analyses on patient cohorts to correlate NLRX1 expression with clinical outcomes. Bioinformatic analyses and immunofluorescence staining of human HNSCC tissues were employed to assess associations between immune cell infiltration, gene expression correlations and PD-L1 levels on antigen-presenting cells (APCs). In vitro experiments were conducted to investigate the regulatory role of NLRX1 on cell proliferation and gene expression profiling by overexpressing or knocking down NLRX1. In vivo studies of subcutaneous tumor models in both immunodeficient and immunocompetent mice were utilized to assess the function of NLRX1 on tumor progression.

RESULTS

The expression NLRX1 is correlated with unfavorable patient outcomes. NLRX1 promotes tumor progression by modulating the immune microenvironment, not directly affecting tumor cell proliferation. Mechanistically, NLRX1 suppresses the type I interferon (IFN-I) pathway by inhibiting STING expression in HNSCC. Notably, tumor cell-intrinsic NLRX1 negatively correlates with PD-L1 expression on APCs in HNSCC. In vivo, NLRX1 knockdown activated STING-IFN-I signaling, upregulated APC PD-L1, suppressed tumor growth, and significantly boosted anti-PD-L1 therapy in murine tumor models.

CONCLUSIONS

NLRX1 mediates immune evasion in HNSCC by downregulating STING protein abundance, suppressing the IFN-I pathway, and decreasing PD-L1 expression of APCs. Targeting NLRX1 offers a promising strategy to overcome ICI resistance and improve immunotherapeutic efficacy in HNSCC.