AXL Kinase Inhibition Promotes Cytosolic DNA Sensor cGAS Activity and Sensitizes Poorly Immunogenic Tumors to Chemo-Immunotherapy

AXL is an important negative regulator of type I IFN responses during viral infections. In the context of tumors, AXL is associated with driving tumor progression, spread, immune evasion, and therapy resistance. AXL regulation of tumor cell-intrinsic IFN responses remains unexplored. We show that AXL suppresses tumor cell-intrinsic IFN responses by inhibiting the cytosolic DNA sensor cGAS via an AKT-dependent pathway. AXL inhibition in combination with chemoimmunotherapy demonstrated potent antitumor effects in poorly immunogenic tumors that are refractory to immunotherapy. The inhibition of AXL correlated with increased cGAMP levels, activation of IFN, and enhanced infiltration of T cells and NK cells into the tumor microenvironment. These findings reveal a novel role for AXL in suppressing IFN within tumors and support AXL targeting as a promising strategy in conjunction with chemoimmunotherapy for treating therapy-resistant tumors.