Serum free fatty acid promotes tumor progression and predicts golidocitinib sensitivity in peripheral T-cell lymphoma

Peripheral T-cell lymphoma (PTCL) is an aggressive and heterogeneous lymphoma subtype with high chemoresistance and poor prognosis. Common peripheral blood disease biomarkers with therapeutic potential are lacking. In this study, we analyzed the serum metabolic profiles of 557 patients with newly diagnosed PTCL, including 278 extranodal natural killer/T-cell lymphoma (NKTCL), 117 patients with nodal T-follicular helper cell lymphoma (nTFHL), 92 with PTCL, not otherwise specified (PTCL-NOS), 36 with anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL), and 34 with ALK-negative ALCL. We identified high free fatty acid (FFA) as an adverse prognostic biomarker across PTCL subtypes. Integrative analysis of transcriptomic and single-cell RNA-sequencing data sets further revealed that serum FFA linked to JAK-STAT signaling activation and a suppressive tumor microenvironment, characterized by increased infiltration of monocytic myeloid-derived suppressor cells (MDSCs) in NKTCL and M2 macrophages in nTFHL and PTCL-NOS, respectively. The selective JAK1 inhibitor golidocitinib showed pronounced antitumor efficacy in coculture systems under palmitic acid-induced high-FFA conditions and in syngeneic and xenograft murine lymphoma models fed with high-fat diet through the JAK-STAT- interleukin-6 (IL-6)/IL-10 axis-mediated inhibition of MDSCs in NKTCL and M2 macrophages in nTFHL and PTCL-NOS, respectively. In alignment with our experimental findings, relapsed or refractory patients with PTCL, who had high serum FFA levels, exhibited superior responses to golidocitinib treatment than those with low serum FFA levels. Collectively, high serum FFA is related to tumor progression and indicates golidocitinib sensitivity, providing novel insights into reprogramming lipid metabolism to dually target the tumor and microenvironment in PTCL.