TFE3‐PD‐L1 axis is pivotal for sunitinib resistance in clear cell renal cell carcinoma

The microphthalmia of bHLH‐LZ transcription factor (MiT/TFE) family chromosomal translocation or overexpression is linked with a poor prognosis in clear cell renal cell carcinoma (ccRCC) with elevated recurrence and drug resistance, but the molecular mechanism is not fully understood. Here, we investigated whether the resistance to sunitinib (Sun), the standard treatment for metastatic ccRCC, is due to up‐regulation of programmed death ligand 1 (PD‐L1) by the transcription factor E3 (TFE3). In this study, we propose that TFE3 but not TFEB is essential for tumour survival which was associated with the poorer survival of cancer patients. We also found a positive correlation between TFE3 and PD‐L1 expression in ccRCC cells and tissues. Sun treatment led to enhanced TFE3 nuclear translocation and PD‐L1 expression. Finally, we observed the therapeutic benefit of Sun plus PD‐L1 inhibition which enhanced CD8+ cytolytic activity and thus tumour suppression in a xenografted mouse model. These data revealed that TFE3 is a potent tumour promoting gene and it mediates resistance to Sun by induction of PD‐L1 in ccRCC. Our data provide a strong rationale to apply Sun and PD‐L1 inhibition jointly as a novel immunotherapeutic approach for ccRCC treatment.