La isoforma C de la proteína quinasa C impulsa la infiltración de macrófagos y media la inmunosupresión en el cáncer...

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and remains the leading cause of cancer-related mortality. Immune checkpoint inhibitors (ICIs) targeting the programmed death-1/programmed death ligand 1 (PD-1/PD-L1) axis can induce durable tumor regression in a subset of NSCLC patients; however, most exhibit resistance to ICIs therapy. Here, we identify the protein kinase Cι (PKCι)) as a biomarker and critical mediator of poor ICIs responsiveness in NSCLC. High PKCι expression correlates with resistance to anti-PD-1 antibody (αPD1) therapy, whereas low PKCι expression are highly sensitive. PKCι-dependent resistance to αPD1 is characterized by increased tumor-associated macrophages (TAMs) infiltration and reduced CD8+T cell numbers. Mechanistically, PKCι regulated Yap1-dependent transcription of CCL7, which recruits TAMs and fosters an immunosuppressive microenvironment. In contrast, Overexpression of PKCι or CCL7 in PKCι-knockdown tumors restores TAMs infiltration and αPD1 resistance. Pharmacological inhibition of PKCι with auranofin (AF) reduces TAMs accumulation and promotes CD8+T cell infiltration by inhibiting the PKCι-Yap1-CCL7 axis. Combination therapy with AF and αPD1 triggers a CD8+T cell-dependent antitumor immune response, thereby controlling tumor growth in situ or subcutaneously. In summary, our study reveals a PKCι-mediated immunosuppressive pathway driving ICIs resistance and support PKCι inhibition as a promising strategy to enhance immunotherapy efficacy in NSCLC.