Associate Research Scientist Univ. of Michigan Med. Sch., United States
Introduction/Rationale: Immune checkpoint blockade (ICB) relies on dendritic cells (DCs) to activate T cells and mediate anti-tumor immunity. However, the impact of key transcription factors, specifically the balance of STAT3 and STAT5 in DCs, on ICB efficacy remains unclear. Tumor microenvironments often promote STAT3 activation, suppressing DC maturation and function, whereas STAT5 activation is associated with enhanced anti-tumor responses. Understanding and modulating this balance may improve immunotherapy outcomes.
Methods: We analyzed single-cell and bulk RNA-seq data from human tumor samples pre- and post-ICB. We performed genetic (knockout, shRNA) and pharmacological (novel PROTAC STAT3 degraders SD-36, SD-2301) interventions in murine and human DCs in vitro and in vivo. We assessed DC maturation, T cell activation, tumor growth, and response to ICB, including in advanced or ICB-resistant tumor models.
Results: We found that ICB reprograms DCs by shifting the STAT3/STAT5 balance toward immunogenic STAT5 activity. STAT3 restrains STAT5-mediated DC maturation. Deleting or degrading STAT3 in DCs promoted antigen presentation, T cell activation, and tumor control. Our STAT3 degraders (SD-36, SD-2301) effectively targeted DCs, enhanced anti-tumor immunity, even in ICB-resistant settings, and synergized with ICB. These effects required both DCs and functional STAT5, and were CD8+ T cell-dependent.
Conclusion: Our findings demonstrate that the interplay between STAT3 and STAT5 in DCs determines anti-tumor immunity and ICB effectiveness. Targeted STAT3 degradation in DCs reprograms them toward immunogenicity, enhances T cell responses, and overcomes resistance to immunotherapy, representing a promising strategy for cancer treatment.
