Abstract
Increased acetyl-coenzyme A (acetyl-CoA) generation facilitates cancer metastasis and represents a critical metabolic characteristic of metastatic cancers. To maintain high acetyl-CoA levels, cancer cells often enhance the uptake of acetate for acetyl-CoA biosynthesis. However, the microenvironmental source of acetate remains largely unknown. Here we demonstrate that acetate is secreted by tumour-associated macrophages (TAMs) and taken up by hepatocellular carcinoma (HCC) cells to support acetate accumulation. Mechanistically, HCC cell-derived lactate activates the lipid peroxidation–aldehyde dehydrogenase 2 (ALDH2) pathway in TAMs, which promotes the TAMs’ acetate production and secretion. Inhibition of ALDH2 or of lipid peroxidation in TAMs abrogates acetate-induced migration of HCC cells in vitro. In an orthotopic HCC model involving male mice, genetic ablation of ALDH2 in TAMs reduces HCC cell acetate levels and HCC lung metastases. Collectively, our findings reveal a metabolic interaction between HCC cells and TAMs—involving lactate, lipid peroxidation and acetate—and position TAMs as an acetate reservoir that drives HCC metastasis.
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The raw numerical source data are published alongside the paper; the other data that support the findings of this study are available from the corresponding authors upon reasonable request. Source data are provided with this paper.
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Acknowledgements
We thank Z.-S. Zhou, L.-F. Yang, D. Ye, Y. Chen, J. Qin and H.-Y. Yin for their helpful discussions on this project. We thank L. Qiu, Z. Li, J.-Y. Wu and Y.-F. Bu from the Institutional Center for Shared Technologies and Facilities of the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, for technical assistance. This work was supported by grants from the National Key R&D Program of China (no. 2022YFA1303000 to M.L.), the National Natural Science Foundation of China (no. 82173132 to M.L., no. 81930074 and no. 91959203 to L.X.Q.; no. 82072696 and no. 82472951 to W.W.Z.).
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M.L. conceived the concept of the study. M.L., L.Q. and W.Z. designed the study. S.W. and C.G. performed the early exploration. L.S., S.F., X.L., Y.B. and Y.C. performed experiments. S.W., C.G., L.S., J.P., H.X. and Y.Z. collected and analysed human HCC samples. Q.L., L.S., S.W. and X.Z. performed the liquid chromatography–mass spectrometry analysis. Q.L. and L.S. performed the stable isotope tracing assay. L.S. conducted the statistical analysis and generated the figures. M.L., L.Q. and W.Z. interpreted the data and wrote the paper.
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Extended data
Extended Data Fig. 1 Acetate levels in HCC tissues and the flow cytometry gating strategy of TAMs.
a, b, The levels of acetate in HCC tumor tissues (a) and tumor-derived interstitial fluid samples (b) in comparison to the corresponding adjacent normal liver. Data are shown as mean ± SEM (n = 7 mice per group) (a), or mean ± SEM (n = 5 mice per group) (b). HCC tumor tissues and normal liver tissues were from Hepa1-6 orthotopic HCC mice model. C57BL/6 J mice were orthotopically injected with Hepa1-6-ZsGreen cells. 14 days later, the mice were sacrificed, and the tumor tissues were used for isolation of primary TAMs, TANs and NCCs by flow cytometry. The flow cytometry gating strategy is shown in (c). TAMs were depleted in Hepa1-6-ZsGreen orthotopic HCC mice model by intraperitoneal injection of clodronate liposomes every 2 days for three times. The depletion efficiencies were then determined by measuring the infiltration of CD45+Ly6G−F4/80+CD11bint cells by flow cytometry (d), and primary Hepa1-6-ZsGreen cells were isolated from tumor tissues by flow cytometry. The flow cytometry gating strategy is shown in (e). Representative images result from at least three independent experiments are shown. P values were determined by unpaired two-tailed Student’s t-tests (a, b).
Extended Data Fig. 2 Validation of induction of TAMs and CAFs and TAMs-induced acetate accumulation in other types of cancer cells.
a, The mRNA levels of marker genes in TAMs generated from THP-1 cell-derived MΦs. b, The mRNA levels of CAFs marker genes in LX2 cell-derived CAFs. c, d, The mRNA levels of marker genes in TAMs generated from RAW264.7 cells or from BMDM. e–g, The acH3 and acH3K9 levels in breast cancer cells (MDA231 and AT3), colorectal cancer cells (HCT116 and MC38) and pancreatic cancer cells (PANC-1 and PanC02) after treatment with TAMs-CM. Data are represented as mean ± s.d. of triplicate experiments (a–d), images are representative of three independent experiments (e–g). P values were determined by unpaired two-tailed Student’s t-tests (a–d).
Extended Data Fig. 3 TAMs does not affect the expression of genes involved in acetate metabolism in HCC cells.
a, b, The mRNA levels of genes involved in acetate metabolism in MHCC-97H cells and Hepa1-6 cells after treatment with TAMs-CM, respectively. Data are shown as mean ± s.d. of triplicate experiments. P values were determined by unpaired two-tailed Student’s t-tests.
Extended Data Fig. 4 Lipid peroxidation-ALDH2 pathway is responsible for acetate production in TAMs.
a, b, The protein levels of ALDH2 and ALDH1B1 in TAMs generated from THP-1 cell-derived MΦs or RAW264.7 cells. c, d, Confirmation of ALDH2 or ALDH1B1 knockdown in THP-1 cells stably expressing with shRNA targeting ALDH2 (shALDH2) or ALDH1B1 (shALDH1B1). e, Immunoblots of ALDH2 protein in BMDM or liver isolated from Aldh2-flox or Aldh2-cKO mice. f, g, Confirmation of Aldh2 or Aldh1b1 knockdown in RAW264.7 cells stably expressing shRNA targeting Aldh2 (shAldh2) or Aldh1b1 (shAldh1b1). h, i, Secreted acetate levels in TAMs with silenced Aldh2 or Aldh1b1 (h) or in TAMs treated with ALDH2 inhibitor (i). j, k, Effects of silencing of ALDH2 on the mRNA levels of IL10 and ARG1 in TAMs and corresponding MΦs. l–q, MDA levels (l, m), Cox1 and Cox2 mRNA levels (n, o) and the lipid peroxidation levels (p, q) in TAMs and corresponding MΦs. Quantitation of the lipid peroxidation levels are shown in q. r, s, Effects of Fer-1 (2 μM) or NAC (5 mM) on the lipid peroxidation levels in TAMs (r) and primary TAMs (s). t, Effects of Aspirin (10 mM) on the MDA generation in TAMs. u–z, As depicted in u and v, TAMs generated from RAW264.7 cells were incubated with exogenous [U-13C]-LA for 36 h with or without etomoxir or NAC, and were subjected to determine labeled carbons in LA (w), AA (x) and secreted acetate (y). The proportion of labelled secreted acetate to labelled AA is shown in z. Scale bar, 20 μm (p, r and s). Data are shown as three biologically independent cell cultures (h, i, l, m, t, w and x), four biologically independent cell cultures (y, z), mean ± s.d. of triplicate experiments (j, k, n and o), or mean ± s.d. of 5 representative pictures (q), images are representative of three independent experiments (a–g, q–s). P values were determined by one-way ANOVA with Tukey’s multiple comparisons test (h, i and t) or unpaired two-tailed Student’s t-tests (j–o and q).
Extended Data Fig. 5 Silencing of ALDH2 expression abrogates acetate-induced migration of HCC cells.
a, b, The effect of ALDH2 silencing on pro-migration capacity of TAMs. Hepa1-6 cells were co-cultured with TAMs generated from RAW264.7 cells. Then, cell migration was determined in Hepa1-6 cells (a), and the relative migrated cell numbers are expressed as the fold change to controls (b). c, The effect of ALDH2 silencing in TAMs on growth of Huh7 cells. Huh7 cells were co-cultured with TAMs generated from THP-1 cell-derived MΦs for 24 h. d–g, The effect of ALDH2 silencing on pro-migration capacity of TAMs. Huh7 cells were incubated with TAMs-CM or TAMs-MP generated from THP-1 cell-derived MΦs, Hepa1-6 cells were incubated with TAMs-CM or TAMs-MP generated from RAW264.7 cells. Then, cell migration was determined in these HCC cells (d, f), and the relative migrated cell numbers are expressed as the fold change to controls (e, g). h, i, The effect of ALDH2 inhibitor on the pro-migration capacity of TAMs on Hepa1-6 cells. Hepa1-6 cells were incubated with CM from CVT-10216 (50 nM)-treated TAMs with or without exogenous acetate, the migration of Hepa1-6 cells were then examined (h). The relative migrated cell numbers are expressed as the fold change to controls (i). j, k, The effects of inhibition of lipid peroxidation on pro-migration capacity of TAMs generated from THP-1 cell-derived MΦs. TAMs-CM were prepared by using TAMs treated with the Fer-1 (2 μM), NAC (5 mM) or Aspirin (10 mM), and the migration of Huh7 cells treated with these TAMs-CM were examined (j). The relative migrated cell numbers are expressed as the fold change to controls (k). Scale bar, 100 μm (a, d, f, h, j). Data are shown as mean ± s.d. of 10 (e, g, i and k) or 8 representative pictures (b) from three biologically independent cell cultures, or five biologically independent cell cultures (c). P values were determined by one-way ANOVA with Tukey’s multiple comparisons test (b, e, g, i and k) or two-way ANOVA with Holm-Sidak’s multiple comparisons test (c). ns, not significant.
Extended Data Fig. 6 Silencing of ALDH2 expression does not lead to the accumulation of oxidized lipids and reactive aldehydes in TAMs.
a–h, The effects of ALDH2 silencing on the levels of intracellular ROS (a), lipid peroxidation (b), intracellular MDA and 4-HNE (c, d), secreted MDA, 4-HNE (e, f) and oxidized lipids (g, h) in TAMs generated from THP-1 cell-derived MΦs. Intracellular ROS levels were measured with DCFH-DA, and the relative ROS levels are expressed as the fold change to controls (a). Quantitation of the lipid peroxidation levels are shown in right of b. Oxidized lipids were determined by LC-MS analysis (g, h). i, The effects of ALDH2 silencing on the expressions of other ALDH family genes in TAMs. Scale bar, 20 μm (b). Data are shown as mean ± s.d. of seven biologically independent cell cultures (a), six biologically independent cell cultures (h), 5 representative pictures from three biologically independent cell cultures (right of b), five biologically independent cell cultures (c, e), four biologically independent cell cultures (d, f, g), or triplicate experiments (i). P values were determined by unpaired two-tailed Student’s t-tests. ns, not significant.
Extended Data Fig. 7 TAMs-CM promotes HCC cells migration by increasing acetyl-CoA levels.
a, b, Confirmation of ACSS2 knockdown (shACSS2) and ACSS1 expression in Huh7 cells. c, The acH3 levels of Huh7 shNT cells and Huh7 shACSS2 cells with or without exogenous acetate. d, Confirmation of ACSS1 and ACSS2 knockdown (shACSS1/2) in MHCC-97H cells. e–g, The effect of TAMs-MP treatment on acH3 levels (e) and migration (f, g) of MHCC-97H shNT cells and MHCC-97H shACSS1/2 cells. The relative migrated cell numbers are expressed as the fold change to controls (g). h, i, The effect of MCT1 inhibitor, AZD3965, on the migration of Huh7 cells with or without exogenous acetate. The migration of Huh7 cells were examined (h). The relative migrated cell numbers are expressed as the fold change to controls (i). Scale bar, 100 μm (f, h). Data are shown as mean ± s.d. of 9 (g), or 10 representative pictures (i) from three biologically independent cell cultures, images are representative of three independent experiments (a–e). P values were determined by one-way ANOVA with Tukey’s multiple comparisons test (g, i).
Extended Data Fig. 8 TAMs-derived acetate promotes HCC cells migration by increasing acH3 levels.
a, b, Huh7 cells were treated with CM from shNT TAMs or shALDH2 TAMs and p300 acetyltransferase inhibitor (C646, 5 μM), and the migration (a, b) or acH3 levels (c) of Huh7 cells were examined. The relative migrated cell numbers are expressed as the fold change to controls (b). d–f, Huh7 cells were treated with CM from shNT TAMs or shALDH2 TAMs and Trichostatin A (TSA, 1 μM), and the migration (d, e) or acH3 levels (f) of Huh7 cells were examined. The relative migrated cell numbers are expressed as the fold change to controls (e). g–i, The effect of knockdown of different KATs on migration and acH3 levels. Huh7 shNT cells, Huh7 shKAT2A cells and Huh7 shKAT5 cells were treated with CM from shNT TAMs or shALDH2 TAMs, and the migration (g, h) or acH3 levels (i) of Huh7 cells were examined. The relative migrated cell numbers are expressed as the fold change to controls (h). j, Immunoblots of TWIST and N-cadherin, and E-cadherin in Huh7 cells treated with CM from shNT TAMs or shALDH2 TAMs. Scale bar, 100 μm (a, d and g). Data are shown as mean ± s.d. of 10 representative pictures from three biologically independent cell cultures (b, e and h), images are representative of three independent experiments (c, f, i and j). P values were determined by one-way ANOVA with Tukey’s multiple comparisons test (b, e and h).
Extended Data Fig. 9 Genetic ablation of ALDH2 in TAMs does not affect the immune cells infiltration, and ACSS1/ACSS2 knockdown limits HCC metastasis.
a–h, Flow cytometry analysis of the infiltration of immune cells in primary tumor tissues from Hepa1-6-ZsGreen orthotopic HCC mice model in Aldh2-flox and Aldh2-cKO mice. Data are represented as mean ± SEM (n = 7 mice per group). i, j, Representative mIHC images using human HCC samples showing tumor areas with high infiltration of ALDH2+ CD163+ TAMs. Yellow and white arrows indicate HCC cells and ALDH2+ CD163+ TAMs respectively (Bottom photos in i, j). Scale bars, 3 mm (the left images), 20 μm (the remaining pictures). k–r, Balb/c-nu/nu mice were orthotopically inoculated with Huh7 shNT cells, Huh7 shACSS2 cells, MHCC-97H shNT cells or MHCC-97H shACSS1/2 cells. At the end point (day 21), the primary tumors were harvested (k, o), tumor volumes were calculated (l, p), spontaneous lung metastases were detected by ex vivo bioluminescence imaging, and the endpoint bioluminescence images (m, q) and the quantification of photon flux of lungs (n, r) are shown. Data are represented as mean ± s.e.m. (n = 7 mice per group) (l, n, p, r). P values were determined by unpaired two-tailed t-test (a–h, l, n, p, r). ns, not significant.
Extended Data Fig. 10 HCC cells-derived lactate induces lipid peroxidation-ALDH2 pathway in TAMs.
a, The lactate concentrations in TCM from MHCC-97H cells and Hepa1-6 cells. b, The mRNA levels of ALDH2 in RAW264.7 cells after treatment with lactate (10 mM). c–e, The effect of lactate on the MDA levels (c) and the lipid peroxidation levels (d) in RAW264.7 cells. Quantitation of the lipid peroxidation levels are shown in e. Scale bar, 20 μm. f, The levels of ROS in RAW264.7 cells after treatment with lactate. Intracellular ROS levels were measured with DCFH-DA. g, h, The mRNA levels of ALDH2 (g) and the levels of MDA (h) were determined in RAW264.7 cells after treatment with lactate and NAC (5 mM). i, j, The mRNA levels of NOX1 and NOX2 in THP-1 cell-derived MΦs (i) or RAW264.7 cells (j) after treatment with lactate. Data are shown as mean ± s.d. of triplicate experiments (b, g, i, j), mean ± s.d. of three biologically independent cell cultures (a, c, h), mean ± s.d. of six biologically independent cell cultures (f), or mean ± s.d. of 5 representative pictures from three biologically independent cell cultures (e). P values were determined by one-way ANOVA with Tukey’s multiple comparisons test (g, h) or unpaired two-tailed Student’s t-tests (b, c, e, f, i, j). ns, not significant.
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Shen, L., Wang, S., Gao, C. et al. Tumour-associated macrophages serve as an acetate reservoir to drive hepatocellular carcinoma metastasis. Nat Metab 7, 2268–2283 (2025). https://doi.org/10.1038/s42255-025-01393-9
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DOI: https://doi.org/10.1038/s42255-025-01393-9
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