TERT promoter mutations or protein overexpression define an aggressive subset with favourable immunotherapeutic response in advanced urothelial carcinoma.

Objective: Telomerase reverse transcriptase (TERT) gene promoter mutation (TPM) is a key non-coding somatic alteration in urothelial carcinoma (UC) that plays a critical role in telomerase activation. Despite its importance, the prognostic value of TPM has shown mixed results in previous studies.

Methods and analysis: This study included 155 UC patients from two local clinical centres and 1652 patients from four public datasets, along with matched clinical annotation. Immunohistochemistry of TERT and immune-related markers was performed on tissue microarrays, and transcriptomic and genomic data were analysed to evaluate immune microenvironment characteristics and mutational profiles associated with TPM. We assessed the association of TPM or TERT overexpression (OE) with clinical outcomes, genomics and immunological profiles across tumour stages.

Results: In early-stage UC, TPM or TERT OE was not significantly associated with patient outcomes. However, in advanced urothelial carcinoma (aUC), TPM or TERT OE was linked to markedly worse overall survival (OS) and a poor response to platinum-based chemotherapy. Notably, despite this unfavourable prognosis, these patients exhibited a more favourable response to anti-PD-1/PD-L1 immunotherapy. aUC with TPM or TERT OE was characterised by an immune-evasive microenvironment, including infiltration of exhausted CD8⁺ T cells and elevated PD-1 and PD-L1 expression. Furthermore, genomic analysis further revealed a higher APOBEC mutational signature and a lower clock-like mutational signature in aUC with TPM or TERT OE.

Conclusion: In this retrospective study, TPM or TERT OE identifies a more aggressive subset of patients with poor OS and an immune-evasive microenvironment but a better response to immunotherapy in aUC.