Improving therapeutic efficacy by targeting adenosine signaling in obese breast cancers

Accumulated adipocytes in obese cancer patients significantly compromise therapeutic efficacy,yet the underlying mechanisms remain largely undefined. Here, we identify an OTUD4-driven proteolyticaxis as a critical regulator of immune suppression in obesity-associated triple-negative breast cancer(TNBC). Hyperactivation of OTUD4 enhances CD73-mediated adenosinergic signaling in cooperationwith TGF-beta, establishing an immunosuppressive tumor microenvironment (TME) enriched with TREM2 + APOE + lipid-laden tumor-associated macrophages (LL-TAMs). This adenosine-rich niche promotes LL-TAM polarization toward a CCL2 + IL6 + efferocytic phenotype, collectively dampening cytotoxic T-cellactivity. Spatial and histologic analyses reveal regional co-expression of TGF-beta, OTUD4, and CD73 withinimmune-suppressed tumor zones that spatially align with LL-TAM clusters. To therapeutically target thispathway, we developed W-DB53, a selective small-molecule inhibitor that disrupts the OTUD4-CD73interaction, depletes LL-TAMs, restores T-cell infiltration, and synergizes with immune checkpointinhibitors (ICIs) in obese TNBC models. These findings establish W-DB53 as a macrophage-remodelingprotein-protein interaction (PPI) inhibitor that reprograms efferocytosis and overcomes obesity-drivenimmune resistance in TNBC.