Targeting Axl favors an antitumorigenic microenvironment that enhances immunotherapy responses by decreasing Hif-1α levels

Significance A significant pool of HER2 + breast cancer patients are either unresponsive or become resistant to standards of care. New therapeutic approaches exploiting the tumor microenvironment, including immunotherapies, are attractive. Hypoxia shapes the tumor microenvironment toward therapy resistance and metastasis. Here, we report a role for AXL receptor tyrosine kinase in the hypoxic response by promoting HIF-1α expression. Interfering with Axl in a preclinical model of HER2 + breast cancer normalizes the blood vessels and promotes a proinflammatory microenvironment that enhances immunotherapy response to reduce the primary and metastatic tumor burdens. Clinical trials so far suggest that achieving immunotherapy responses in HER2 + cancers might be challenging, and our data might provide an important insight to circumvent a roadblock.