Inflammatory signaling drives SQSTM1-dependent suppression of interferon-γ–induced MHC class I surface expression

An immune-inflamed tumor microenvironment is characterized by the coexistence of interferon-γ (IFN-γ) and inflammatory cytokines, yet how these opposing signals are integrated by cancer cells to regulate tumor immunogenicity remains poorly understood. Here, we investigated interleukin-1β (IL-1β) on IFN-γ–induced major histocompatibility complex class I (MHC-I) expression in non–small cell lung cancer (NSCLC) cells using molecular and cell biological approaches. IL-1β suppressed IFN-γ–induced surface MHC-I expression despite preserved or enhanced expression of antigen presentation–related genes, indicating post-transcriptional regulation. This effect emerged 12–24 h after stimulation and was accompanied by accelerated MHC-I turnover without altering total protein abundance. RNA sequencing identified selective induction of autophagy-related genes specifically under combined IFN-γ and IL-1β stimulation. Immunofluorescence and biochemical analyses demonstrated intracellular redistribution of MHC-I to autophagosome–lysosome compartments. Mechanistically, the selective autophagy receptor SQSTM1 associated with MHC-I and was required for its surface downregulation, whereas depletion of NBR1 or inhibition of autophagy or lysosomal function failed to restore MHC-I expression, indicating a nonredundant role for SQSTM1. These findings identify post-translational MHC-I trafficking as a previously underappreciated regulatory layer linking inflammatory signaling to the canonical IFN-γ–MHC-I axis and reveal an SQSTM1-dependent mechanism controlling MHC-I surface availability under immune-inflamed tumor conditions.