Abstract
Lung adenocarcinoma (LUAD), the most prevalent form of lung cancer, is characterized by aggressive growth, immune resistance, and high tumor heterogeneity. Here, we demonstrate that genetic loss of protein kinase Cι (PKCι), which is found in ∼20% of LUAD patients, alters the trajectory of mouse Kras/Trp53-driven LUAD tumors from one resembling lung development to one mimicking lung regeneration. As a result, a major subset of tumor cells with PKCι loss exhibit cellular senescence and transcriptional similarities to the pre-AT1 transitional cell state (PATS) observed during alveolar regeneration after lung injury. Senescent PATS-like tumor cells inhibit cellular plasticity through stable proliferation arrest and induce formation of tertiary lymphoid structures (TLSs) that enhance anti-tumor immunity and patient responses to immune therapies. Importantly, human LUADs harboring genetic PKCι loss also contain TLSs and PATS-like tumor cells. Therefore, PKCι expression in mouse and human LUAD dictates tumor trajectory, cellular plasticity, and the immune microenvironment.