{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T21:47:03Z","timestamp":1785793623624,"version":"3.56.0"},"reference-count":16,"publisher":"Pleiades Publishing Ltd","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Dokl Biochem Biophys"],"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Triple-negative breast cancer (TNBC) is characterized by an aggressive clinical course and extremely limited targeted therapy options. One of the key drivers of immunosuppression in the tumor microenvironment is the polarization of tumor-associated macrophages (TAMs) towards the M2 phenotype. In the present study, we investigated the effect of insulin-like growth factor 2 (IGF2)\u2014the primary ligand of the IGF1R receptor and a target of the inhibitory protein IGFBP6\u2014on the transcriptional profile of macrophages polarized in vitro from the THP-1 cell line. We demonstrate that IGF2 exerts fundamentally different effects depending on the baseline functional state of the macrophages: in immature (M0) and M2-polarized cells, it induces the expression of pro-inflammatory genes, whereas in M1 macrophages it triggers pronounced immunosuppressive reprogramming. These findings suggest that IGFBP6, by inhibiting IGF2, may sustain an anti-tumor immune response within the TNBC microenvironment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1134\/s160767292660034x","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T08:31:46Z","timestamp":1785745906000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Insulin-Like Growth Factor 2 Modulates Macrophage Polarization: the Role of the IGF2\u2013IGFBP6 Axis"],"prefix":"10.1134","author":[{"given":"D. A.","family":"Averinskaya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Yu.","family":"Shkurnikov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"137","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"7844_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H. Sung","year":"2021","unstructured":"Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., and Bray, F., Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA\u2014Cancer J. Clin., 2021, vol. 71, no. 3, pp.\u00a0209\u2013249. https:\/\/doi.org\/10.3322\/caac.21660","journal-title":"CA\u2014Cancer J. Clin."},{"key":"7844_CR2","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1146\/annurev-pathol-042420-093238","volume":"17","author":"F. Derakhshan","year":"2022","unstructured":"Derakhshan, F. and Reis-Filho, J.S., Pathogenesis of triple-negative breast cancer, Annu. Rev. Pathol.: Mech. Dis., 2022, vol. 17, no. 1, pp. 181\u2013204. https:\/\/doi.org\/10.1146\/annurev-pathol-042420-093238","journal-title":"Annu. Rev. Pathol.: Mech. Dis."},{"key":"7844_CR3","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/nrclinonc.2016.217","volume":"14","author":"A. Mantovani","year":"2017","unstructured":"Mantovani, A., Marchesi, F., Malesci, A., Laghi, L., and Allavena, P., Tumour-associated macrophages as treatment targets in oncology, Nat. Rev. Clin. Oncol., 2017, vol. 14, no. 7, pp. 399\u2013416. https:\/\/doi.org\/10.1038\/nrclinonc.2016.217","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"7844_CR4","doi-asserted-by":"publisher","unstructured":"Averinskaya, D., Semenov, I., and Shkurnikov, M.Yu., IGFBP6 expression correlates with macrophage presence in triple-negative breast cancer tumors, Curr. Drug Ther., 2026, vol. 21, no. 5, e15748855416908. https:\/\/doi.org\/10.2174\/0115748855416908251120055038","DOI":"10.2174\/0115748855416908251120055038"},{"key":"7844_CR5","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1038\/nrc2536","volume":"8","author":"M. Pollak","year":"2008","unstructured":"Pollak, M., Insulin and insulin-like growth factor signalling in neoplasia, Nat. Rev. Cancer, 2008, vol. 8, no. 12, pp. 915\u2013928. https:\/\/doi.org\/10.1038\/nrc2536","journal-title":"Nat. Rev. Cancer"},{"key":"7844_CR6","doi-asserted-by":"publisher","unstructured":"Wang, X., Lin, L., Lan, B., Wang, Yu., Du, L., Chen, X., Li, Q., Liu, K., Hu, M., Xue, Yu., Roberts, A.I., Shao, Ch., Melino, G., Shi, Yu., and Wang, Yi., IGF2R-initiated proton rechanneling dictates an anti-inflammatory property in macrophages, Sci. Adv., 2020, vol. 6, no. 48, p. abb7389. https:\/\/doi.org\/10.1126\/sciadv.abb7389","DOI":"10.1126\/sciadv.abb7389"},{"key":"7844_CR7","doi-asserted-by":"publisher","unstructured":"Lu, H., Yu, X., Xu, Zh., Deng, J., Zhang, M.J., Zhang, Yi., and Sun, Sh., Prognostic value of IGFBP6 in breast cancer: focus on glucometabolism, Technol. Cancer Res. Treat., 2024, vol. 23, 15330338241271998. https:\/\/doi.org\/10.1177\/15330338241271998","DOI":"10.1177\/15330338241271998"},{"key":"7844_CR8","doi-asserted-by":"publisher","unstructured":"Nikulin, S., Zakharova, G., Poloznikov, A., Raigorodskaya, M., Wicklein, D., Schumacher, U., Nersisyan, S., Bergquist, J., Bakalkin, G., Astakhova, L., and Tonevitsky, A., Effect of the expression of ELOVL5 and IGFBP6 genes on the metastatic potential of breast cancer cells, Front. Genet., 2021, vol. 12, 662843. https:\/\/doi.org\/10.3389\/fgene.2021.662843","DOI":"10.3389\/fgene.2021.662843"},{"key":"7844_CR9","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.biochi.2025.03.010","volume":"234","author":"M. Silkina","year":"2025","unstructured":"Silkina, M., Razumovskaya, A., Kulagin, T., Fatkulin, A., Klycheva, K., Olkhovik, D., Averinskaya, D., Kolo-deeva, O., Kolodeeva, O., Tonevitsky, A., and Nikulin, S., Divergent ferroptotic pathways in breast cancer cells: IGFBP6-regulated mitochondrial lipid peroxidation under erastin and omega-3 DHA treatment, Biochimie, 2025, vol. 234, pp. 48\u201361. https:\/\/doi.org\/10.1016\/j.biochi.2025.03.010","journal-title":"Biochimie"},{"key":"7844_CR10","doi-asserted-by":"publisher","unstructured":"Freeman, P., Bellomo, G., Ireland, L., Abudula, M., Luckett, T., Oberst, M., Stafferton, R., Ghaneh, P., Halloran, Ch., Schmid, M.C., and Mielgo, A., Inhibition of insulin-like growth factors increases production of CXCL9\/10 by macrophages and fibroblasts and facilitates CD8+ cytotoxic T cell recruitment to pancreatic tumours, Front. Immunol., 2024, vol. 15, 1382538. https:\/\/doi.org\/10.3389\/fimmu.2024.1382538","DOI":"10.3389\/fimmu.2024.1382538"},{"key":"7844_CR11","doi-asserted-by":"publisher","unstructured":"Nikulin, S., Razumovskaya, A., Poloznikov, A., Zakharova, G., Alekseev, B., and Tonevitsky, A., ELOVL5 and IGFBP6 genes modulate sensitivity of breast cancer cells to ferroptosis, Front. Mol. Biosci., 2023, vol. 10, 1075704. https:\/\/doi.org\/10.3389\/fmolb.2023.1075704","DOI":"10.3389\/fmolb.2023.1075704"},{"key":"7844_CR12","doi-asserted-by":"publisher","first-page":"2263","DOI":"10.1161\/circulationaha.116.021805","volume":"133","author":"Yu. Higashi","year":"2016","unstructured":"Higashi, Yu., Sukhanov, S., Shai, S.-Y., Danchuk, S., Tang, R., Snarski, P., Li, Zh., Lobelle-Rich, P., Wang, M., Wang, D., Yu, H., Korthuis, R., and Delafontaine, P., Insulin-like growth factor-1 receptor deficiency in macrophages accelerates atherosclerosis and induces an unstable plaque phenotype in apolipoprotein E\u2013deficient mice, Circulation, 2016, vol. 133, no.\u00a023, pp. 2263\u20132278. https:\/\/doi.org\/10.1161\/circulationaha.116.021805","journal-title":"Circulation"},{"key":"7844_CR13","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1186\/s12918-014-0098-y","volume":"8","author":"D. Tian","year":"2014","unstructured":"Tian, D. and Kreeger, P.K., Analysis of the quantitative balance between insulin-like growth factor (IGF)-1 ligand, receptor, and binding protein levels to predict cell sensitivity and therapeutic efficacy, BMC Syst. Biol., 2014, vol. 8, no. 1, p. 98. https:\/\/doi.org\/10.1186\/s12918-014-0098-y","journal-title":"BMC Syst. Biol."},{"key":"7844_CR14","doi-asserted-by":"publisher","first-page":"614","DOI":"10.3389\/fimmu.2014.00614","volume":"5","author":"N. Wang","year":"2014","unstructured":"Wang, N., Liang, H., and Zen, K., Molecular mechanisms that influence the macrophage m1-m2 polarization balance, Front. Immunol., 2014, vol. 5, p. 614. https:\/\/doi.org\/10.3389\/fimmu.2014.00614","journal-title":"Front. Immunol."},{"key":"7844_CR15","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1111\/j.1365-2249.2010.04210.x","volume":"162","author":"M. Acharya","year":"2010","unstructured":"Acharya, M., Borland, G., Edkins, A.L., Maclellan, L.M., Matheson, J., Ozanne, B.W., and Cushley, W., CD23\/Fc\u03b5RII: molecular multi-tasking, Clin. Exp. Immunol., 2010, vol. 162, no. 1, pp. 12\u201323. https:\/\/doi.org\/10.1111\/j.1365-2249.2010.04210.x","journal-title":"Clin. Exp. Immunol."},{"key":"7844_CR16","doi-asserted-by":"publisher","first-page":"787","DOI":"10.14218\/jcth.2022.00392","volume":"11","author":"L. Yao","year":"2023","unstructured":"Yao, L., Hu, X., Yuan, M., Zhang, Q., Liu, P., Yang, L., Dai, K., and Jiang, Yi., IGF2-NR4A2 signaling regulates macrophage subtypes to attenuate liver cirrhosis, J. Clin. Transl. Hepatol., 2023, vol. 11, pp. 787\u2013799. https:\/\/doi.org\/10.14218\/jcth.2022.00392","journal-title":"J. Clin. Transl. Hepatol."}],"container-title":["Doklady Biochemistry and Biophysics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1134\/S160767292660034X.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1134\/S160767292660034X","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1134\/S160767292660034X.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T21:02:57Z","timestamp":1785790977000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1134\/S160767292660034X"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,3]]},"references-count":16,"alternative-id":["7844"],"URL":"https:\/\/doi.org\/10.1134\/s160767292660034x","relation":{},"ISSN":["1607-6729","1608-3091"],"issn-type":[{"value":"1607-6729","type":"print"},{"value":"1608-3091","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,3]]},"assertion":[{"value":"15 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 May 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 May 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 August 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The research protocol was approved by the Commission for Ethical Review of Empirical Research Projects of the Faculty of Biology and Biotechnology, HSE University.","order":1,"name":"Ethics","label":"ETHICS APPROVAL AND CONSENT TO PARTICIPATE","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The authors of this work declare that they have no conflicts of interest.","order":2,"name":"Ethics","label":"CONFLICT OF INTEREST","group":{"name":"EthicsHeading","label":"Ethics"}}]}}