Background: Histological transformation of follicular lymphoma (tFL) represents an aggressive subtype characterized by a complex and immunosuppressive tumor immune microenvironment (TIME). Therefore, it is urgent to investigate the characteristics of TIME and develop more effective immunotherapy strategies for tFL patients.

Methods: Using single-cell RNA sequencing, a high-resolution landscape of the entire TIME ecosystem of follicular lymphoma (FL) and tFL patients is depicted. Findings were validated by multiplex immunofluorescence (mIF) staining, in vitro assays, and a mouse model.

Results: Compared to FL patients, tFL patients exhibited a higher proportion of exhausted CD8+T cells expressing checkpoint receptors such as LAG3, CTLA4, PD-1, and HAVCR2. Notably, Galectin-3 expression was acquired by tumor cells after transformation, leading to enhanced Galectin-3–LAG3 interactions with CD8⁺T cells, as confirmed by mIF staining. In co-culture experiments, Galectin-3-overexpressing tumor cells impaired CD8⁺ T cell proliferation and cytotoxicity, inducing an exhausted phenotype. Treatment with the Galectin-3 inhibitor GB1107 rescued T cell function. Similar T cell dysfunction and GB1107 response were observed in Galectin-3-overexpressing mouse xenograft model. Additionally, we identified an accumulation of MDSC-like monocytes and M2-like macrophages in tFL patients, further contributing to immune suppression.

Conclusion: Galectin-3 drives T cell exhaustion and reshapes the immune microenvironment in tFL patients, promoting immune evasion and disease progression. Targeting Galectin-3 may represent a promising immunotherapeutic strategy for tFL patients.

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2025
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