研究背景：腫瘤微環境中免疫細胞的重塑被認為是驅動肺癌進展與產生治療抗性的關鍵因素；其中，巨噬細胞在腫瘤微環境中具有高度可塑性，能根據外在刺激轉化為促發炎的 M1 表型或具免疫抑制功能的 M2 表型。本團隊先前研究指出，M2 表型腫瘤相關巨噬細胞 (tumor-associated macrophages, TAMs) 可透過 Rab37 小分子G蛋白 (small GTPase) 介導的分泌路徑釋放IL-6免疫抑制性細胞激素，抑制 T 細胞的毒殺功能，進而促進腫瘤惡化並降低化療效益。然而，Rab37如何參與巨噬細胞 M2 極化的分子調控機制仍不清楚。
研究目的：本研究以單細胞RNA定序 (single-cell RNA sequencing)，深入解析在野生型 (wild type, WT) 與Rab37基因剔除 (knockout, KO) 小鼠之肺腫瘤微環境中 (tumor microenvironment, TME)，巨噬細胞族群的組成與功能差異。進一步探討Rab37以傳統與非傳統的囊泡運輸途徑在巨噬細胞極化中的調控角色，並評估其如何影響肺癌的進程與對化療的抗性，期望為免疫治療策略提供新的分子靶點。
研究結果：分析結果顯示，肺癌誘導的啟動子去甲基化上調了 TAMs 中 Rab37 的表達。進一步機制探討發現，Rab37 根據其不同的核苷酸結合狀態（GDP-bound 與 GTP-bound）展現雙重調控功能。GDP-bound Rab37 會與訊息傳導分子 STAT1 結合並將其滯留於細胞質中，抑制 STAT1 進入細胞核並阻斷第一型干擾素（type I interferon, IFN）訊號及其下游干擾素刺激基因（interferon-stimulated genes, ISGs）的表達，進而削弱巨噬細胞的抗腫瘤能力並促進免疫抑制性腫瘤微環境的建立。另外，GTP-bound Rab37 促進 IL-33 受體 ST2L 的囊泡運輸與膜表現，加強 IL-33/ST2L/NF-κB 訊號並形成正回饋迴路，驅動 M2 型免疫抑制巨噬細胞極化，進一步促進腫瘤進展與化療抗性。
結論：整體而言，Rab37 透過促進 ST2L 的細胞膜運送並同時抑制干擾素訊號，協同驅動腫瘤相關巨噬細胞免疫抑制重編程，促進有利於腫瘤生長與治療抗性的免疫抑制微環境。這些發現不僅揭示 Rab37 在腫瘤免疫中的多重關鍵角色，也為肺癌免疫治療提供潛在的標靶策略。

Background: Remodeling of immune cells within the tumor microenvironment (TME) is considered a major contributor to cancer progression and therapy resistance. Among these, tumor-associated macrophages (TAMs) exhibit remarkable plasticity and can be polarized into either pro-inflammatory M1 or immunosuppressive M2 phenotypes in response to environmental cues. Our previous study suggests that M2-like TAMs promote immunosuppression and chemoresistance through the small GTPase Rab37-regulated secretion of IL-6 cytokines. However, the molecular mechanisms underlying Rab37-mediated M2 polarization in macrophages remain largely unclear.
Purpose: This study aimed to investigate the impact of Rab37 on macrophage polarization and function in the lung TME by comparing wild-type (WT) and Rab37 knockout (KO) mice. Using single-cell RNA sequencing (scRNA-seq), we defined the transcriptional heterogeneity of TAMs and selected potential Rab37 effectors and pathways to delineate the role of Rab37 in modulating macrophage-driven tumor progression and chemoresistance.
Results: Our analysis revealed that Rab37 expression is upregulated in TAMs through lung cancer-induced promoter demethylation. Mechanistically, Rab37 exerts dual regulatory functions depending on its nucleotide-bound status (GDP-bound and GTP-bound). The GDP-bound form of Rab37 interacts with STAT1 and retains it in the cytoplasm, thereby inhibiting STAT1 nuclear translocation and suppressing type I interferon (IFN) signaling and interferon-stimulated gene (ISG) expression. This pathway attenuates the anti-tumor activity of macrophages and facilitates the establishment of an immunosuppressive TME. In addition, the GTP-bound form of Rab37 promotes the trafficking and membrane presentation of ST2L, the receptor for interleukin-33 (IL-33), enhancing IL-33/ST2L/NF-κB signaling and reinforcing a positive feedback loop that drives M2-like macrophage polarization. This dual mechanism supports tumor progression and contributes to chemotherapy resistance.
Conclusions: Collectively, our study identifies Rab37 as a critical regulator of macrophage polarization and tumor immune suppression via its distinct GDP- and GTP-bound functions. These findings highlight Rab37 as a potential therapeutic target for reprogramming TAMs and overcoming immune evasion in lung cancer.

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