Abstract Peripheral T-cell lymphomas (PTCL) are aggressive mature T-cell malignancies associated with poor responses to standard therapies and frequent relapse, even in the era of targeted treatments. These outcomes highlight the critical need for biology-driven therapeutic strategies. PTCL is characterized by a complex tumor microenvironment (TME), in which malignant T-cells often represent only a minor fraction within a diverse immune and stromal ecosystem. While prior studies have largely focused on tumor-intrinsic features, the role of TME in driving lymphoma progression and therapeutic resistance remains largely unknown. Using a murine Vav1-myo1f model, we previously demonstrated that malignant T-cells actively shape an M2 macrophage-rich TME, and that targeting tumor-associated macrophages (TAMs) yields significant anti-lymphoma effects, supporting a critical role for the TME in PTCL pathogenesis. Here, we performed an integrated multiomic analysis of 29 human PTCL biopsies, including T follicular helper lymphoma (TFHL) and PTCL-NOS, and six reactive lymphoid controls using single-nucleus RNA sequencing, bulk RNA sequencing, and targeted mutational profiling. After quality control, 230, 174 cells were analyzed. Unsupervised clustering identified 45 transcriptionally distinct TME cell states spanning benign T-cell, B-cell, myeloid, endothelial, and stromal compartments, many not previously described in PTCL. Tumors exhibited extensive remodeling of both cellular composition and transcriptional programs, including depletion of antigen-presenting macrophages, expansion of TAM states, enrichment of exhausted CD8+ T cells, and profound stromal reprogramming. Systems-level analysis identified recurrent multicellular ecosystems defined by coordinated gene expression programs across immune and stromal compartments. These ecosystems were associated with distinct cytokine signaling networks and included two mutually exclusive TME states: an inflammatory macrophage/FDC-associated ecosystem and an immunosuppressive M2 macrophage/cancer-associated fibroblast (CAF) ecosystem driven by TGFβ signaling. Together, these data demonstrate that PTCL is characterized not only by altered lineage abundance but also by reproducible remodeling of intra-lineage transcriptional programs, including the emergence of tumor-specific cellular states within the microenvironment. These structured ecosystems reflect coordinated cross-talk between malignant T-cells and surrounding immune and stromal populations and are shaped by distinct cytokine signaling circuits. Ligand-receptor analysis identified TGFβ-TGFBR interactions as central mediators of lymphoma-TME communication, and functional validation in a murine model showed that TGFβ blockade significantly reduced tumor burden and proliferation. Collectively, these findings provide new insights into PTCL biology and establish a foundation for TME-informed therapeutic strategies, with potential implications for patient stratification and targeted intervention. Citation Format: Wen-Hsuan Wendy Lin, Anqi Wang, Jean-Baptiste Reynier, Bobby B. Shih, Laura Quevedo, Craig R. Soderquist, Ryan Najac, Jianhua Wang, Hannah Miller, Cindy Ma, Anouchka P. Laurent, Ruth Alonso Alonso, Alyssa Bouska, Javeed Iqbal, Govind Bhagat, Adolfo Ferrando, Raul Rabadan, Teresa Palomero. Microenvironmental ecosystems in peripheral T-cell lymphomas reveal therapeutic vulnerabilities abstract. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7 (3Suppl): Abstract nr A056.
Lin et al. (Wed,) studied this question.