Stimulator of interferon genes agonist augmented antitumor immunity of osimertinib in <i>Egfr</i> ‐mutated lung cancer

Epidermal growth factor receptor ( EGFR )‐mutant non‐small‐cell lung cancers (NSCLCs) lack effective immunotherapy due to a noninflamed tumor microenvironment (TME). We previously reported that EGFR tyrosine‐kinase‐inhibitor (TKI) induced CD8 + T‐cell immunity, which was insufficient for tumor eradication. We evaluated the potential of combining EGFR‐TKI with stimulator of interferon genes (STING) agonists in activating a systemic antitumor response. Using a syngeneic mouse model of genetically engineered Egfr ‐mutant NSCLC, we evaluated the antitumor effects of STING agonist ADU‐S100, alone and combined with osimertinib. Immunohistochemistry and flow cytometry were used to assess the TME. Osimertinib alone enhanced CD8 + T‐cell infiltration but not Natural Killer (NK) cell infiltration. ADU‐S100 injection alone modestly suppressed tumor growth with increasing CD8 + /NK cell infiltration in the TME, but lacked an abscopal effect. Combining ADU‐S100 with osimertinib significantly enhanced the antitumor effects and CD8 + /NK cell infiltration. Depletion of either CD8 + or NK cells reduced the combination effect. Crucially, the combination induced an abscopal effect accompanied by PD‐1 + /CD8 + cell infiltration. Combining osimertinib with a STING agonist augmented innate and adaptive immunity, inducing systemic antitumor responses in EGFR ‐mutant NSCLC.