Abstract Background The proto-oncogene rearranged during transfection (RET) mutation can influence tumor immunogenicity and regulate immune responses through multiple pathways. Herein, we performed an in-depth bioinformatic and clinical analysis to systematically evaluate the attibutes of RET mutation and their interconnections with outcomes in pan-cancer immune checkpoint blockade (ICB) therapeutic interventions. Methods The predictive significance of RET mutation was evaluated in a discovery cohort comprising 1406 patients with six tumor types, and the findings were verified in an independent cohort of 1524 individuals representing nine tumor types. Utilizing The Cancer Genome Atlas (TCGA), we retrieved multi-omics data and further investigated both intrinsic and extrinsic immune response mechanisms behind the RET mutation. Results Among 2930 immune checkpoint inhibitor (ICI)-treated patients with 11 tumor types, the presence of RET mutation showed a significant association with favorable overall survival (HR, 0.60; 95% CI, 0.48-0.75; P 0.001) and objective response rate (44.9% vs. 25.7%; P 0.001). Furthermore, the frequencies of six mutational signatures related to immunotherapy outcomes, changed significantly in RET-mutant tumors. Additional multi-omics analysis on intrinsic and extrinsic immune landscapes elucidated that the RET mutation could enrich immune cell infiltration besides improving tumor immunogenicity, alongside immune responses. Conclusions RET mutation may enhance anti-tumor immunity and function as an independent biomarker for promising outcomes across multiple cancer types treated with ICB. These findings have the potential to inform clinical decision-making, guide personalized immunotherapy strategies, and contribute to the advancement of precision oncology.
Cai et al. (Sat,) studied this question.