High Endothelial Venules in Small Cell Lung Cancer: Prognostic Subtypes and Therapeutic Implications for Immunoradiotherapy

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy with an immunosuppressive tumor microenvironment, and current immunotherapy provides limited benefit. This highlights the need to identify microenvironmental features enabling effective immune responses. High endothelial venules (HEVs) are critical for lymphocyte recruitment and antitumor immunity, yet their roles in SCLC remain poorly understood. To investigate HEV-related features among SCLC patients, five bulk RNA-seq datasets comprising 583 tumor samples were integrated. HEV-related signatures stratified SCLC patients into two subtypes, C1 and C2, associated with HEV-high and HEV-low states, respectively. C1 showed a more immune-active microenvironment and superior prognosis. Consistently, using single-cell RNA-seq data and validating the findings by immunofluorescence staining in an independent cohort of 80 patients with SCLC, we confirmed that the presence of HEV structures was associated with a favorable prognosis. We further established a prognostic model and identified five genes, PDCD1, CXCL9, ITK, ITGAL, and SH2D1A, as key favorable prognostic factors. A nomogram incorporating age, tumor stage, and the prognostic model was also developed and exhibited satisfactory performance. Additionally, we explored the translational potential of promoting HEV formation as a therapeutic strategy in SCLC. In murine SCLC models, radiotherapy combined with immunotherapy promoted HEV formation and enhanced antitumor efficacy. HEVs appeared to serve as a critical link underlying the therapeutic synergy between radiotherapy and immunotherapy. Collectively, these findings highlight the biological and clinical relevance of HEVs in SCLC and suggest that combination strategies aimed at promoting HEV formation may help overcome the limited efficacy of immunotherapy.