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<p>Tumor-associated Macrophages (TAMs) are highly plastic immune cells that shape the tumor microenvironment (TME) and influence cancer progression. However, the molecular determinants governing their functional heterogeneity remain incompletely understood. In this study, we identify Rab37 as a key regulator that remodels the states of macrophages within the lung TME. Single-cell RNA sequencing revealed that <i>Rab37</i> wild-type (WT) tumors were enriched in immunosuppressive <i>Spp1</i><sup><i>+</i></sup> TAMs, whereas <i>Rab37</i> knockout (KO) tumors contained a higher proportion of <i>Thbs1</i><sup><i>+</i></sup> TAMs, suggesting Rab37-dependent shifts in macrophage programming. Mechanistically, Rab37 promoted osteopontin (OPN) secretion, which activated STAT3 signaling to establish an autocrine feedback loop that sustained <i>Spp1</i> expression and induced M2-like polarization. Paracrine OPN signaling further enhanced lung cancer cell proliferation, migration, and invasion. In clinical lung cancer specimens, CD163<sup>+</sup>/Rab37<sup>+</sup>/OPN<sup>+</sup> TAMs correlated with recurrence and poor survival, and multivariate analysis confirmed their independent prognostic value. Together, these findings demonstrate that Rab37 governs macrophage phenotype and function by orchestrating OPN/STAT3 signaling, thereby reinforcing an immunosuppressive TME and promoting lung cancer progression. Targeting the Rab37–OPN axis may thus represent a promising therapeutic strategy.</p>

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Rab37-mediated OPN secretion enriches SPP1+ macrophages through autocrine–paracrine signaling to drive lung tumor progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月14日

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  • You-En Yang,
  • Yu-An Lin,
  • Lun-Ling Ling,
  • I-Ying Kuo,
  • Wan-Ting Kuo,
  • Hsuan Liu,
  • Yi-Ching Wang

摘要

Tumor-associated Macrophages (TAMs) are highly plastic immune cells that shape the tumor microenvironment (TME) and influence cancer progression. However, the molecular determinants governing their functional heterogeneity remain incompletely understood. In this study, we identify Rab37 as a key regulator that remodels the states of macrophages within the lung TME. Single-cell RNA sequencing revealed that Rab37 wild-type (WT) tumors were enriched in immunosuppressive Spp1+ TAMs, whereas Rab37 knockout (KO) tumors contained a higher proportion of Thbs1+ TAMs, suggesting Rab37-dependent shifts in macrophage programming. Mechanistically, Rab37 promoted osteopontin (OPN) secretion, which activated STAT3 signaling to establish an autocrine feedback loop that sustained Spp1 expression and induced M2-like polarization. Paracrine OPN signaling further enhanced lung cancer cell proliferation, migration, and invasion. In clinical lung cancer specimens, CD163+/Rab37+/OPN+ TAMs correlated with recurrence and poor survival, and multivariate analysis confirmed their independent prognostic value. Together, these findings demonstrate that Rab37 governs macrophage phenotype and function by orchestrating OPN/STAT3 signaling, thereby reinforcing an immunosuppressive TME and promoting lung cancer progression. Targeting the Rab37–OPN axis may thus represent a promising therapeutic strategy.