Through our human and mouse studies and analysis of the publicly available big data, we have demonstrated PDLIM2 as a bona fide tumor suppressor and its epigenetic repression and downstream STAT3/NF-κB RelA oncogenic activation as a main driver of lung cancer pathogenesis and resistance to anti-PD-1 and chemotherapeutic therapies that can be targeted as monotherapy or adjunctive therapy of anti-PD-1 and chemotherapeutic drugs. The gene discussed is STAT3; the disease is lung cancer.