Mutation of rearranged during transfection (RET) is associated with enhanced tumor immunogenicity and favorable outcomes in pan-cancer immunotherapy.

[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 attributes 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 6 tumor types, and the findings were verified in an independent cohort of 1524 individuals representing 9 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 < .001) and objective response rate (44.9% vs. 25.7%; P < .001). Furthermore, the frequencies of 6 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] Rearranged during transfection 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.