Cbx5 Target to Boost Immunotherapy Efficacy in Small Cell Lung Cancer

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine carcinoma with a very poor prognosis and accounts for approximately 15% of all lung cancers. Although immunotherapy is now a key component of standard care for SCLC, the clinical benefits remain modest. Growing evidence indicates that epigenetic regulators play important roles in antitumor immunity and in controlling responses to immunotherapy response. In this study, we report Cbx5 as a potential epigenetic regulator of antitumor immunity in SCLC. Our preliminary data suggests that Cbx5 loss may enhance the responses of SCLC tumors to anti-PD-1 therapy in immunocompetent mice. Our preliminary analysis suggests that Cbx5 loss may activate immune response related genes/pathways, while its depletion may derepress endogenous retroviruses in SCLC. Cbx5 deficiency may potentially remodel the tumor microenvironment by converting SCLC from an immune-cold to an immune-hot state. In summary, our findings indicate that Cbx5 may function as a central epigenetic regulator of immune response and immune evasion in SCLC, revealing a potential epigenetic target to enhance responsiveness to immunotherapy. Additional studies are ongoing to validate these findings and further characterize the immunoregulatory mechanisms governed by Cbx5. Citation Format: Hong Cao, Yiting Li, Jiajia Gu, Yuan Hao, Ziyang Wang, Benjamin A. Nacev, Kwok-Kin Wong, Hua Zhang. Cbx5 as a potential target to enhance immunotherapy in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5718.