肿瘤相关巨噬细胞（TAM）浸润增加会促进肿瘤进展，并与各种肿瘤类型的不良预后相关。我们的研究发现，非小细胞肺癌 (NSCLC) 中 Pim-1 原癌基因 (PIM1) 的消融可抑制 TAM 浸润并防止其极化为 M2 表型，从而重塑肿瘤免疫微环境 (TME)。 PIM1 对巨噬细胞趋化性和极化产生影响的主要机制涉及 CC 基序趋化因子配体 2 (CCL2)。 PIM1 的表达水平与 NSCLC 中 CCL2 的高表达呈正相关，导致患者的总体生存率较差。从机制上讲，PIM1 缺陷通过靶向核因子 kappa beta (NF-κB) 信号传导促进 TAM 重编程，并抑制 NSCLC 细胞的 CCL2 反式激活。 CCL2 分泌减少会阻碍 TAM 积累及其向促肿瘤表型的极化。此外，Pim1 和 PD-1 的双重阻断协同抑制肿瘤生长，使巨噬细胞复极化，并增强抗 PD-1 抗体的功效。总的来说，我们的研究结果阐明了 PIM1 在 NSCLC TME 内协调 TAM 中的关键作用，并强调了 PIM1 抑制作为增强癌症免疫疗法疗效的策略的潜力。© 2024。作者获得 Springer 独家许可自然有限公司。

Elevated infiltration of tumor-associated macrophages (TAMs) drives tumor progression and correlates with poor prognosis for various tumor types. Our research identifies that the ablation of the Pim-1 proto-oncogene (PIM1) in non-small cell lung cancer (NSCLC) suppresses TAM infiltration and prevents them from polarizing toward the M2 phenotype, thereby reshaping the tumor immune microenvironment (TME). The predominant mechanism through which PIM1 exerts its impact on macrophage chemotaxis and polarization involves CC motif chemokine ligand 2 (CCL2). The expression level of PIM1 is positively correlated with high CCL2 expression in NSCLC, conferring a worse overall patient survival. Mechanistically, PIM1 deficiency facilitates the reprogramming of TAMs by targeting nuclear factor kappa beta (NF-κB) signaling and inhibits CCL2 transactivation by NSCLC cells. The decreased secretion of CCL2 impedes TAM accumulation and their polarization toward a pro-tumoral phenotype. Furthermore, Dual blockade of Pim1 and PD-1 collaboratively suppressed tumor growth, repolarized macrophages, and boosted the efficacy of anti-PD-1 antibody. Collectively, our findings elucidate the pivotal role of PIM1 in orchestrating TAMs within the TME of NSCLC and highlight the potential of PIM1 inhibition as a strategy for enhancing the efficacy of cancer immunotherapy.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.