Locus-Specific Human Endogenous Retrovirus ERVK18 Expression Indicates an Inflamed Microenvironment and Favorable Immunotherapy Outcome in Small Cell Lung Cancer

PURPOSE: Despite the clinical adoption of immunotherapy in small cell lung cancer (SCLC), reliable biomarkers predicting clinical benefit are limited. Although HERV-K (HML-2) subfamily has been reported to modulate tumor immune response in multiple malignancies, its functional role in SCLC remains poorly defined, particularly the association with an inflamed microenvironment and favorable immunotherapy outcomes. EXPERIMENTAL DESIGN: The expression profile of locus-specific HERV-K was identified by TELESCOPE in the IMpower133 (n =271) and PKUPH cohort (n = 40). Immunohistochemistry and RNA-fluorescence in situ hybridization were performed on a tissue microarray (n = 48) to validate the expression of HERV-K transcripts. Single-cell RNA sequencing and multiplex immunohistochemistry, including PhenoCycler-Fusion, were used to characterize tumor immune microenvironment. RESULTS: Although the HERV-K subfamily as a whole lacked prognostic value for immunotherapy in SCLC, a locus-specific HERV-K transcript, ERVK18, was associated with improved outcomes and exhibited the strongest positive correlation with immune-related signatures, representing multiple immune-activated pathways and increased immune cell infiltration. Single-cell and spatial analysis further revealed that high ERVK18 expression indicated elevated cytotoxicity signatures in T cells, along with enhanced spatial proximity between tumor and T cells. In the IMpower133 cohort, high ERVK18 expression was not only associated with better prognosis within atezolizumab+chemotherapy group, but also predicted improved overall survival in patients treated with atezolizumab+chemotherapy versus chemotherapy alone, confirming ERVK18 as a dual prognostic and predictive biomarker for first-line PD-L1 inhibitor response in SCLC. CONCLUSIONS: Elevated expression of ERVK18 represents inflamed microenvironment and indicates favorable immunochemotherapy prognosis of patients in SCLC.