Integrative Multiomics and Single-Cell Profiling Identify TNFRSF1A<sup>+</sup> Macrophages as a Prognostic and Therapeutic Target in Diffuse Large B-cell Lymphoma

The tumor microenvironment plays a critical role in therapeutic resistance in diffuse large B-cell lymphoma (DLBCL), yet actionable targets within the immune cells remain largely undefined. Through integrative multiomics profiling, we identified tumor necrosis factor receptor superfamily member 1A (<i>TNFRSF1A</i>) as a key prognostic determinant associated with predicted R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) resistance, specifically localizing its expression to tumor-associated macrophages (TAMs). Mechanistic investigation via ligand-receptor network analysis and in silico perturbation revealed that TNFRSF1A⁺ TAMs sustain a pro-oncogenic and immunosuppressive niche, by driving nuclear factor-κB (NF-κB)-dependent B-cell activating factor (BAFF) secretion and immune checkpoint ligand (programmed death-ligand 1/programmed death-ligand 2) expression. Pharmacogenomic screening coupled with molecular dynamics simulations identified curcumin as a potential modulator of TNFRSF1A-associated signaling. Subsequent experimental validation using small interfering RNA-mediated knockdown and coculture assays confirmed that disrupting the macrophage-intrinsic TNFRSF1A/NF-κB/BAFF axis eliminated the protective support provided by TAMs to lymphoma cells. Additionally, a novel risk model derived from the TNFRSF1A⁺ TAM transcriptional signature demonstrated robust predictive accuracy for patient outcomes across independent cohorts. Our findings elucidate the role of TNFRSF1A⁺ TAMs in driving DLBCL progression, highlight the TNFRSF1A/NF-κB/BAFF axis as a vulnerability in the DLBCL microenvironment, and propose curcumin as a viable therapeutic strategy to disrupt this supportive microenvironment.