Osteopontin links acquired resistance to hypoxia-inducing antiangiogenics with refractoriness to anti-PD-L1 agents in breast cancer [II]

These agents can either normalize or exacerbate tumor vascular abnormality and hypoxia. The mechanisms of resistance remain unclear in the latter setting.

By integrating data from mouse models and clinical trials, we show that hypoxia-inducing anti-VEGF therapy upregulates programmed cell death ligand 1 (PD-L1), yet fails to sensitize tumors to PD-L1 blockade. Mechanistically, early hypoxic stress triggers epithelial osteopontin (Spp1) production, which recruits monocytes and skews macrophages toward M2 states, suppressing T-cell cytotoxicity. Pharmacologic Spp1 depletion impedes the development of hypoxia, M2 infiltration, restores T-cell activity and enables synergy between antiangiogenics and anti-PD-L1.