The molecules PD-L1 and MHC class I are central to how tumors avoid immune detection and resist therapies targeting the PD-1/PD-L1 axis. In this work, we found that higher levels of every microRNA belonging to the miR-23a/27a/24-2 group were linked to shorter patient survival, stronger immune suppression, and failure of PD-1/PD-L1 inhibitors among individuals with non-small cell lung cancer (NSCLC). When these miRNAs were overexpressed, they boosted PD-L1 by suppressing Cbl proto-oncogene B (CBLB) and reduced MHC-I by raising eukaryotic initiation factor 3B (eIF3B) through inhibition of microphthalmia-associated transcription factor (MITF). We also showed that continuous production of the miR-23a/27a/24-2 miRNAs in NSCLC depends on active Wnt/β-catenin signaling, which strengthens the attachment of transcription factor 4 (TCF4) to the cluster’s promoter. Remarkably, blocking the eIF3B pathway with drugs greatly enhanced the response to PD-1/PD-L1 inhibitors in NSCLC patients, showing strong miR-23a/27a/24-2 cluster activity, primarily by restoring MHC-I without lowering the elevated PD-L1 caused by the cluster. In conclusion, our study reveals how the miR-23a/27a/24-2 miRNAs sustain their own presence and the specific ways they drive immune avoidance and treatment resistance in tumors. We further introduce an innovative treatment option for NSCLC cases with abundant miR-23a/27a/24-2 cluster miRNAs.
