Background: Targeting tumor-associated macrophages (TAMs) is a promising immunotherapy for cancers, but current strategies are limited due to strategic caveats. PU.1 is a transcription factor required for macrophage generation and differentiation. To date, the effect of PU.1 inhibition on solid tumors is unknown.Methods: This study examines the anti-tumor effect of PU.1 inhibition and its mechanism using the small-molecule DB2313 in mouse melanoma and breast tumor models.Results: We found that inhibition of PU.1 by DB2313 suppresses B16-OVA melanoma and 4T1 breast tumor growth in mice. In the melanoma tumor model, DB2313 enhanced tumor recruitment of CD4+T helper 1 (Th1) and cytotoxic T/natural killer (NK) cells by targeting TAMs. Transcriptome and targeted gene expression analyses revealed that PU.1 inhibition by DB2313 and small-interference RNAs enhances CXCL9 expression in bulk tumors, TAMs, and bone marrow-derived macrophages. The anti-tumor effects of DB2313 were abolished by depleting macrophages with clodronate or inhibiting the CXCL9-CXCR3 chemokine axis using CXCL9- or CXCR3-neutralizing antibodies.Conclusions: These results suggest that pharmacological inhibition of PU.1 suppresses tumor growth by at least promoting the infiltration of lymphocytes into tumors through the CXCL9-CXCR3 chemokine axis. Our study establishes a framework for developing TAM-modulating immunotherapies by targeting the transcriptional factor PU.1.
背景：靶向肿瘤相关巨噬细胞（TAMs）是一种前景广阔的癌症免疫疗法，但现有策略因存在策略性缺陷而受限。PU.1是巨噬细胞生成与分化所必需的转录因子。迄今为止，抑制PU.1对实体瘤的作用尚不明确。 方法：本研究通过小分子化合物DB2313在小鼠黑色素瘤和乳腺肿瘤模型中，探究了抑制PU.1的抗肿瘤效应及其作用机制。 结果：我们发现DB2313对PU.1的抑制能有效抑制小鼠B16-OVA黑色素瘤和4T1乳腺肿瘤的生长。在黑色素瘤模型中，DB2313通过靶向TAMs增强了肿瘤对CD4+辅助性T细胞1（Th1）及细胞毒性T细胞/自然杀伤（NK）细胞的募集作用。转录组及靶向基因表达分析显示，DB2313与小干扰RNA对PU.1的抑制均能提升整体肿瘤组织、TAMs及骨髓源性巨噬细胞中CXCL9的表达水平。当使用氯膦酸盐清除巨噬细胞，或采用CXCL9/CXCR3中和抗体阻断CXCL9-CXCR3趋化因子轴时，DB2313的抗肿瘤效应被完全消除。 结论：这些结果表明，药物抑制PU.1可通过至少促进CXCL9-CXCR3趋化因子轴介导的淋巴细胞向肿瘤浸润，从而抑制肿瘤生长。本研究为通过靶向转录因子PU.1开发TAM调控型免疫疗法建立了理论框架。
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