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Summary Cancer immunotherapy focuses on inhibitors of checkpoint proteins, such as programmed death ligand 1 (PD-L1). Unlike RAS-mutated lung cancers, EGFR mutant tumors have a generally low response to immunotherapy. Because treatment outcomes vary by EGFR allele, intrinsic and microenvironmental factors may be involved. Among all non-immunological signaling pathways surveyed in patients’ datasets, EGFR signaling is best associated with high PD-L1. Correspondingly, active EGFRs stabilize PD-L1 transcripts and depletion of PD-L1 severely inhibits EGFR-driven tumorigenicity and metastasis in mice. The underlying mechanisms involve the recruitment of phospholipase C-γ1 (PLC-γ1) to a cytoplasmic motif of PD-L1, which enhances PLC-γ1 activation by EGFR. Once stimulated, PLC-γ1 activates calcium flux, Rho GTPases, and protein kinase C, collectively promoting an aggressive phenotype. Anti-PD-L1 antibodies can inhibit these intrinsic functions of PD-L1. Our results portray PD-L1 as a molecular amplifier of EGFR signaling and improve the understanding of the resistance of EGFR+ tumors to immunotherapy., Graphical abstract, Highlights • Unlike promoter-mediated PD-L1 induction by IFN-γ, EGFR rapidly stabilizes PD-L1 mRNA • Once induced, PD-L1 enhances metastasis in vivo and chemotaxis toward EGF • PD-L1 physically binds with and enhances activation of phospholipase C-γ1 by EGFR • PLC-γ1 binds a PD-L1’s cytoplasmic segment implicated in protection from cytotoxicity, Unlike patients expressing mutant KRAS, patients with lung cancer harboring EGFR mutations are relatively resistant to immunotherapy. Because responses differ by EGFR allele, Ghosh et al. investigate the EGFR-to-PD-L1 axis. They report a three-way collaboration among EGFR, PD-L1, and phospholipase C-γ1. Targeting this triad may enhance responses to immunotherapy.