A comprehensive analysis of HMGB1 as a biomarker for predicting immunotherapy efficacy in small cell lung cancer

Background: High mobility group box 1 protein (HMGB1) is known to be associated with progression and poor prognosis of several solid tumors. However, its role in small cell lung cancer (SCLC) remains unclear. Therefore, we intend to provide the first systematically analysis of HMGB1 as a prognostic and immunotherapy predictive biomarker in SCLC. Methods: Public datasets and self-tested transcriptomic/proteomic data from SCLC surgical samples were integrated to screen target molecules through differential analysis. HMGB1 expression was validated in multicenter cohorts using qPCR and tissue microarray immunohistochemistry (IHC). Public data and in-house data were utilized to investigate the association between HMGB1 and SCLC transcriptional subtypes as well as clinicopathological features. The impact of HMGB1 on the tumor immune microenvironment was evaluated through transcriptomic enrichment analysis, single-cell sequencing and IHC. In the NCC cohort of over 180 SCLC patients treated with immune checkpoint inhibitors (ICIs), the relationships between HMGB1 and ORR, PFS, and OS were analyzed, with a prediction model constructed. Finally, serum HMGB1 levels were measured by ELISA to assess its value as a secreted protein biomarker. Results: Multi-omics screening and clinical validation confirmed that HMGB1 was significantly overexpressed in SCLC tumor tissues, and high expression was associated with shorter OS and DFS. HMGB1 expression showed no significant association with the four SCLC subtypes but correlated with high-risk factors such as advanced tumor stage. Transcriptomic enrichment and single-cell analyses revealed that high HMGB1 expression correlated with an immunosuppressive "cold tumor" microenvironment. In the ICIs-treated cohort, patients with high HMGB1 expression exhibited significantly shortened PFS and OS. ROC analysis demonstrated that HMGB1 outperformed traditional markers in predicting treatment response. Multivariate Cox regression confirmed HMGB1 as an independent predictor of immunotherapy efficacy in SCLC. Serum HMGB1 levels were consistent with tumor tissue expression, validating its liquid biopsy potential. Conclusions: HMGB1 is an independent risk factor for SCLC prognosis. Its high expression shapes an immunosuppressive microenvironment and mediates resistance to immunotherapy. HMGB1 shows a good potential to serves as a novel biomarker for predicting immunotherapy efficacy in SCLC, with clinical applicability for both tissue-based and blood-based detection.