The stroma of solid tumors can exclude or limit immune infiltration, or lead to the recruitment of tumor-promoting rather than tumor-attacking immune cells. This finding was reported by Jayaprakash et al. in this issue of the JCI, and it was particularly prominent in the hypoxic zones of tumors in the transgenic adenocarcinoma of the mouse prostate (TRAMP) cancer models. A current clinical goal of immune checkpoint blockade (ICB) is to extend its utility to more patients by converting immunologically “cold” tumors that do not provoke a strong immunological response to “hot” tumors that are invaded by swarms of T cells. When the underlying cause is hypoxia linked, the therapeutic combination of simultaneous targeting of hypoxia and immune checkpoints merits exploration in future clinical trials.