Differential Modulation of the DR5–JNK–PD-L1 Signaling Axis by TRiC/CCT Subunits CCT7 and CCT2 Shapes Tumor Immune Evasion in Lung Adenocarcinoma

While the chaperonin-containing TCP-1 (CCT) complex is essential for proteostasis, the distinct roles of individual subunits in tumor immune regulation remain unclear. Here, we identify CCT7 as a previously unrecognized regulator of immune evasion in lung adenocarcinoma (LUAD). Integrative analyses of TCGA and GEO cohorts revealed that CCT7 is markedly upregulated in LUAD and is associated with poor patient prognosis. Functional studies demonstrated that CCT7 knockdown inhibited tumor cell proliferation and migration and enhanced cisplatin-induced apoptosis, yet paradoxically impaired T-cell activation. Mechanistically, transcriptomic and biochemical analyses revealed that CCT7 depletion activated the DR5–MKK4–JNK–c-Jun signaling cascade, resulting in the transcriptional upregulation of PD-L1. Disruption of DR5 or JNK signaling effectively abrogated PD-L1 induction. In contrast, CCT2 depletion exerted the opposite effect by suppressing the DR5–JNK–c-Jun–PD-L1 signaling axis and enhancing T-cell activation. Collectively, these findings reveal unexpected functional divergence among TRiC/CCT subunits and identify the CCT7–DR5–JNK–c-Jun signaling axis as a previously unrecognized mechanism regulating PD-L1-mediated immune evasion, highlighting the potential therapeutic relevance of this signaling axis in LUAD.