TAF1 Suppresses MHC-I Expression and Correlates with Poor Immunotherapy Response in Small Cell Lung Cancer

Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by an intrinsic resistance to immunotherapy, primarily due to its low immunogenicity and immune-cold tumor microenvironment. The mechanisms underlying this resistance remain poorly understood. Methods: A systematic screen of 796 epigenetic regulators was performed to identify candidate genes associated with effector CD8+ T cell infiltration and clinical outcomes following chemoimmunotherapy in SCLC. This analysis integrated several public SCLC datasets, including single-cell RNA sequencing (scRNA-seq) data from 20 SCLC tumors, bulk RNA-seq data from the IMpower133 cohort, proteomic profiles from the TU-SCLC cohort, and an independent scRNA-seq dataset of 39 SCLC tumors. In vitro and in vivo functional experiments were conducted to investigate the role of the candidate genes in SCLC. Results: The epigenetic regulator TAF1 emerged as a key candidate, with its expression negatively correlating with effector CD8+ T cell infiltration in SCLC. Clinically, patients with low TAF1 expression in tumors showed better outcomes following atezolizumab-based chemoimmunotherapy, particularly in ASCL1-high tumors. Additionally, TAF1 expression was inversely correlated with MHC-I expression. Knockdown of TAF1 in SCLC cells restored MHC-I expression, suppressed tumor growth in immunocompetent mice, and increased CD8+ T cell infiltration. Conclusions: TAF1 functions as a potential epigenetic suppressor of MHC-I expression in SCLC. Targeting TAF1 may represent a promising therapeutic strategy to enhance immunotherapy efficacy in SCLC.