Stat5 And Stat3 Balance Shapes Dendritic Cell Function And Tumour Immunity Jiajia Zhou1 by Jiajia Zhou1, 2, Kole Tison1, 2, 3, 4, Haibin Zhou5, Longchuan Bai5, Ranjan Kumar Acharyya5, instant download after payment.

Immune checkpoint blockade (ICB) has transformed cancer therapy1,2. The efcacy of immunotherapy depends on dendritic cell-mediated tumour antigen presentation, T cell priming and activation3,4. However, the relationship between the key transcription factors in dendritic cells and ICB efcacy remains unknown. Here we found that ICB reprograms the interplay between the STAT3 and STAT5 transcriptional pathways in dendritic cells, thereby activating T cell immunity and enabling ICB efcacy. Mechanistically, STAT3 restrained the JAK2 and STAT5 transcriptional pathway, determining the fate of dendritic cell function. As STAT3 is often activated in the tumour microenvironment5, we developed two distinct PROTAC (proteolysis-targeting chimera) degraders of STAT3, SD-36 and SD-2301. STAT3 degraders efectively degraded STAT3 in dendritic cells and reprogrammed the dendritic cell–transcriptional network towards immunogenicity. Furthermore, STAT3 degrader monotherapy was efcacious in treatment of advanced tumours and ICB-resistant tumours without toxicity in mice. Thus, the crosstalk between STAT3 and STAT5 transcriptional pathways determines the dendritic cell phenotype in the tumour microenvironment and STAT3 degraders hold promise for cancer immunotherapy.