By application of clinical specimen analyses, multi‐omics approaches, and in vivo mouse models, this work demonstrates that EGFR mutations elicited adenosine production through the ERK/c‐Jun signaling axis in tumor cells, establishing an immunosuppressive TME that impeded maturation and antigen presentation of DCs, and in turn weakened CD8+ T cell activation. The gene discussed is EGFR; the disease is neoplasm.