Combination of golidocitinib with chidamide for peripheral T-cell lymphoma: Possible mechanisms and therapeutic potential in inhibiting tumor proliferation and modulating the immune microenvironment

Abstract Background: Peripheral T-cell lymphoma (PTCL) is an aggressive and highly heterogeneous subtype of non-Hodgkin's lymphoma (NHL) derived from post-thymic mature T/NK cells, characterized by poor clinical outcomes and limited therapeutic options. As a novel highly selective JAK1 inhibitor, Golidocitinib has shown potent anti-tumor potential in some PTCL subtypes. This study confirmed the core role of Golidocitinib in the treatment of PTCL, and proposed an innovative strategy of Golidocitinib combined with Chidamide, aiming to break through the limitations of monotherapy and provide a synergistic new therapeutic path for PTCL by simultaneously targeting the intrinsic signaling pathway of tumor cells and the immunosuppressive barrier of the microenvironment. Based on these preclinical findings, we initiated an exploratory clinical evaluation of this combination regimen in four patients with PTCL.Methods: Four classical PTCL cell lines (human T-lymphocytic leukemia cells, Sezary syndrome, ALK+ anaplastic large cell lymphoma, NK/T-cell lymphoma) were treated with Golidocitinib and Chidamide with specified concentration and time gradients, respectively, cell viability was determined by CCK8 assay and 24H IC50 was calculated. Then, four cell lines were treated with Golidocitinib and Chidamide in a fixed ratio, and the combined index (CI) was calculated based on the Chou-Talalay method. For NK/T cell lymphoma (NKTCL) cell lines with significant synergistic effects, RNA sequencing was performed after Golidocitinib single agent, Chidamide single agent and combined drug treatment (2H/12H/24H) to analyze the cytokine expression dynamics. The transwell co-culture model of THP-1-derived macrophages and NKTCL cells was further established, the tumor cell monoculture group, tumor cell monotherapy group (Golidocitinib or Chidamide), macrophage monoculture group, co-culture group and co-culture dosing group (Golidocitinib, Chidamide monotherapy and combination) were set up, and the polarization of macrophages was observed after 48 hours of co-culture, and the tumor cells in the co-culture model were counted and flow cytometry (Annexin V/ PI double staining) to evaluate the effect of Golidocitinib monotherapy and its combination in the tumor immune microenvironment. Subsequently, we evaluated the clinical efficacy of golidocitinib (150 mg once daily) combined with chidamide (20 mg twice weekly) in four patients with PTCL. The cohort included two chemo-free first-line treatment patients (1 PTCL-NOS, 1 AITL) and two fourth-line treatment patients (1 PTCL-NOS, 1 AITL).Results: In PTCL cell lines, Golidocitinib targeted inhibition of the JAK/STAT3 pathway and significantly reduced the expression of pro-inflammatory factors (IL-6, IL-10, TNF-α, IFN-γ) and induced apoptosis in tumor cells. Importantly, the combination of Golidocitinib and Chidamide showed a significant synergistic mechanism: at the cellular level, the combination enhanced antiproliferative activity in a dose-dependent manner (CI < 1); at the microenvironment level, when NKTCL cells were co-cultured with macrophages, Golidocitinib monotherapy could partially overcome the microenvironmental protection to induce apoptosis and reverse the M2 polarization of tumor-associated macrophages, while the combination could amplify this effect - the tumor apoptosis rate of the combination group in the co-culture system far exceeded that of the single agent and single culture dosing group, and the cell count simultaneously confirmed the synergistic killing effect. Building on these preclinical findings, we translated this combination regimen into clinical practice. Two chemo-free first-line treatment patients achieved partial responses (PR) after two cycles, while two fourth-line treatment patients attained complete remission (CR) following four cycles.Conclusion: This translational study demonstrates Golidocitinib's dual PTCL therapeutic mechanism—inhibiting JAK/STAT3-driven tumor proliferation while reprogramming the immunosuppressive microenvironment. The drug's synergy with Chidamide is evidenced by dose-dependent cytotoxicity (CI<1), macrophage polarization reversal, and enhanced apoptosis induction in preclinical models, mirrored by clinical responses across all four PTCL patients (including refractory cases achieving complete remission). These consistent bench-to-bedside outcomes position the Golidocitinib-Chidamide combination as a promising new PTCL treatment paradigm.