{"doi":"10.1093/jimmun/vkaf283.264","title":"Balance between STAT5 and STAT3 determines dendritic cell function and tumor immunity 2337","abstract":"Abstract Description Immune checkpoint blockade (ICB) has transformed cancer therapy. Immunotherapy efficacy depends on dendritic cell (DC)-mediated tumor antigen presentation, T-cell priming and activation. However, the relationship between the key transcription factors in DCs and ICB efficacy remains unknown. Here, we discover ICB reprogrammed the interplay between the STAT3- and STAT5-transcriptional pathways in DCs, thereby activating T-cell immunity and enabling ICB efficacy. Mechanistically, STAT3 restrained the JAK2- and STAT5-transcriptional pathway, determining the fate of DC function. As STAT3 is often activated in the tumor microenvironment (TME), we designed two types of specific PROTAC degraders of STAT3, SD-36 and SD-2301. STAT3-degraders effectively degraded STAT3 in DCs and reprogramed the DC-transcriptional network toward immunogenicity. Furthermore, STAT3-degrader monotherapy was efficacious in treating advanced tumors and ICB-resistant tumors without toxicity in mice. Thus, the crosstalk between the STAT3- and STAT5-transcriptional pathways determines the DC phenotype in the TME and STAT3 degradation holds promise for cancer immunotherapy. Funding Sources Supported in part by research grants from the Breast Cancer Research Foundation, the U.S., NIH/NCI R01 grants (CA217648, CA123088, CA099985, CA193136, CA152470, and CA244509), and the NIH/NCI through the University of Michigan Rogel Cancer Center Grant (CA46592). J.-X.L. and W.J.L. are supported by the Division of Intramural Research, the National Heart, Lung, and Blood Institute, the NIH. 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