Novel post-translational modification learning signature reveals B4GALT2 as an immune exclusion regulator in lung adenocarcinoma

Background Lung adenocarcinoma (LUAD) presents significant challenges in prognosis and treatment efficacy evaluation. While post-translational modifications are known to influence tumor progression, their prognostic value in LUAD remains largely unexplored. Methods We developed a post-translational modification learning signature (PTMLS) using machine learning techniques, analyzing data from 1231 LUAD patients across seven global cohorts. The signature’s efficacy in predicting immunotherapy response was evaluated using 12 immunotherapy cohorts spanning multiple cancer types (n=1201). An in-house LUAD tissue cohort (n=171) was used to validate beta-1,4-galactosyltransferase 2’s (B4GALT2’s) prognostic significance. The role of B4GALT2 in immune exclusion was investigated through in vivo and in vitro experiments. Results The established PTMLS exhibited exceptional predictive capabilities in LUAD patient outcomes, surpassing the efficacy of 98 existing LUAD prognostic indicators. The system’s predictive value was validated across diverse malignancy categories for immunotherapeutic response assessment. From a biological perspective, significant correlations were observed between PTMLS and immunological parameters, whereby elevated PTMLS levels were characterized by attenuated immune responses and immunologically cold neoplastic features. Within the PTMLS framework, B4GALT2 was identified as a crucial molecular component (r=0.82, p<0.05), and its heightened expression was linked to unfavorable clinical outcomes in LUAD cases, particularly in specimens exhibiting CD8-depleted phenotypes. The spatial distribution patterns between B4GALT2 and immune cell populations, specifically CD8+ T lymphocytes and CD20+ B lymphocytes, were elucidated through multiplexed immunofluorescence analysis. Laboratory investigations subsequently established B4GALT2’s regulatory influence on LUAD cellular expansion in both laboratory cultures and animal models. Significantly, suppression of B4GALT2 was found to enhance CD8+ T lymphocyte populations and their functional status, thereby potentiating anti-programmed cell death protein 1 immunotherapeutic efficacy in animal studies. This phenomenon was characterized by reduced CD62L+CD8 T lymphocyte levels alongside elevated GZMB+/CD44+/CD69+CD8 T cell populations. Conclusion The developed PTMLS system represents an effective instrument for individualized prognostic evaluation and immunotherapy stratification in both LUAD and diverse cancer populations. The identification of B4GALT2 as a previously unrecognized oncogenic factor involved in immune exclusion presents a novel therapeutic avenue for LUAD treatment and immunotherapy optimization.