Resveratrol reprograms ARG1⁺ microglia to remodel the immunosuppressive microenvironment in primary CNS lymphoma via secretion cytokine

Abstract Primary central nervous system lymphoma (PCNSL) is a CNS-restricted lymphoma with poor prognosis. Despite sharing pathological features with systemic diffuse large B-cell lymphoma (DLBCL), PCNSL exhibits unique molecular mutation patterns, highlighting the critical role of the intracranial tumor microenvironment (TME). However, the role of microglia within TME remains poorly understood. Here, integrative analysis of single-cell transcriptomic data from systemic DLBCL and PCNSL reveals a distinct TME in PCNSL characterized by a heightened immunosuppressive state via microglia. Here, we identify a subpopulation of ARG1⁺ microglia enriched in the PCNSL tumor core, representing activated morphology and reduced branching complexity. Functionally, these microglia exhibit enhanced cytokine secretion via upgrading PI3K-AKT signal pathway, thereby remodeling the TME and ultimately promoting tumor progression. Targeting this microglia subtype with resveratrol, a bioactive small molecule, resulted in significant tumor suppression in vivo and vitro, accompanied by reduced expression of immunosuppressive cytokines and functional reprogramming of microglia. Collectively, our findings identify ARG1⁺ microglia as key orchestrators of the immunosuppressive TME in PCNSL through secretion cytokine and highlight microglia-targeted modulation by resveratrol as a potential therapeutic strategy.