Features of tumor microenvironment in HER2-positive urothelial carcinoma and its implications for immunotherapy resistance.

Both multiplex IF and TCGA analyses consistently demonstrated that high HER2 expression is associated with reduced infiltration of CD4 + T cells, CD8 + T cells, B cells, and M2 macrophages, together with a decreasing trend in multiple immune checkpoint-related molecules, including CTLA-4, PD-1, PD-L1, and STING.

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In the corresponding phase II study of trastuzumab deruxtecan, response rates varied across IHC/FISH-defined subgroups, and patients with HER2 amplification showed a trend toward greater benefit, suggesting that FISH-confirmed ERBB2 amplification may improve selection of UC patients likely to respond to HER2-ADC therapy [ 35 ].

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