References
[1]. Chouari, T. et al. Advances in Immunotherapeutics in Pancreatic Ductal Adenocarcinoma. Cancers 15, 4265 (2023).
[2]. Ilic, M. & Ilic, I. Epidemiology of pancreatic cancer. World J. Gastroenterol. 22, 9694 (2016).
[3]. Klein, A. P. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat. Rev. Gastroenterol. Hepatol. 18, 493–502 (2021).
[4]. Ho, T. T. B. et al. Combination of gemcitabine and anti-PD-1 antibody enhances the anticancer effect of M1 macrophages and the Th1 response in a murine model of pancreatic cancer liver metastasis. J. Immunother. Cancer 8, e001367 (2020).
[5]. Zhu, Y. et al. CSF1/CSF1R Blockade Reprograms Tumor-Infiltrating Macrophages and Improves Response to T-cell Checkpoint Immunotherapy in Pancreatic Cancer Models. Cancer Res. 74, 5057–5069 (2014).
[6]. Locati, M., Curtale, G. & Mantovani, A. Diversity, Mechanisms, and Significance of Macrophage Plasticity. Annu. Rev. Pathol. Mech. Dis. 15, 123–147 (2020).
[7]. Wynn, T. A., Chawla, A. & Pollard, J. W. Macrophage biology in development, homeostasis and disease. Nature 496, 445–455 (2013).
[8]. Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).
[9]. Wu, Y. et al. Macrophage cell membrane-based nanoparticles: a new promising biomimetic platform for targeted delivery and treatment. J. Nanobiotechnology 20, 542 (2022).
[10]. Cai, H., Zhang, Y., Wang, J. & Gu, J. Defects in Macrophage Reprogramming in Cancer Therapy: The Negative Impact of PD-L1/PD-1. Front. Immunol. 12, 690869 (2021).
[11]. Ruffell, B. & Coussens, L. M. Macrophages and Therapeutic Resistance in Cancer. Cancer Cell 27, 462–472 (2015).
[12]. DeNardo, D. G. & Ruffell, B. Macrophages as regulators of tumour immunity and immunotherapy. Nat. Rev. Immunol. 19, 369–382 (2019).
[13]. Ngambenjawong, C., Gustafson, H. H. & Pun, S. H. Progress in tumor-associated macrophage (TAM)-targeted therapeutics. Adv. Drug Deliv. Rev. 114, 206–221 (2017).
[14]. Dai, E. et al. Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein. Autophagy 16, 2069–2083 (2020).
[15]. Mehla, K. & Singh, P. K. Metabolic Regulation of Macrophage Polarization in Cancer. Trends Cancer 5, 822–834 (2019).
[16]. Fendl, B., Berghoff, A. S., Preusser, M. & Maier, B. Macrophage and monocyte subsets as new therapeutic targets in cancer immunotherapy. ESMO Open 8, 100776 (2023).
[17]. Wei, C. et al. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol. Cancer 18, 64 (2019).
[18]. Wu, K. et al. Redefining Tumor-Associated Macrophage Subpopulations and Functions in the Tumor Microenvironment. Front. Immunol. 11, 1731 (2020).
[19]. Seyfried, T. N. & Huysentruyt, L. C. On the Origin of Cancer Metastasis. Crit. Rev. Oncog. 18, 43–73 (2013).
[20]. Cao, L., Meng, X., Zhang, Z., Liu, Z. & He, Y. Macrophage heterogeneity and its interactions with stromal cells in tumour microenvironment. Cell Biosci. 14, 16 (2024).
[21]. Zhang, X., Ji, L. & Li, M. O. Control of tumor-associated macrophage responses by nutrient acquisition and metabolism. Immunity 56, 14–31 (2023).
[22]. Zhang, X., Ji, L. & Li, M. O. Control of tumor-associated macrophage responses by nutrient acquisition and metabolism. Immunity 56, 14–31 (2023).
[23]. Gao, J., Liang, Y. & Wang, L. Shaping Polarization Of Tumor-Associated Macrophages In Cancer Immunotherapy. Front. Immunol. 13, 888713 (2022).
[24]. Mills, C. D., Lenz, L. L. & Harris, R. A. A Breakthrough: Macrophage-Directed Cancer Immunotherapy. Cancer Res. 76, 513–516 (2016).
[25]. Wang, H., Yung, M. M. H., Ngan, H. Y. S., Chan, K. K. L. & Chan, D. W. The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression. Int. J. Mol. Sci. 22, 6560 (2021).
[26]. Li, M. et al. Metabolism, metabolites, and macrophages in cancer. J. Hematol. Oncol.J Hematol Oncol 16, 80 (2023).
[27]. Halbrook, C. J. et al. Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer. Cell Metab. 29, 1390-1399.e6 (2019).
[28]. Menjivar, R. E. et al. Arginase 1 is a key driver of immune suppression in pancreatic cancer. eLife 12, e80721 (2023).
[29]. Kuen, J., Darowski, D., Kluge, T. & Majety, M. Pancreatic cancer cell/fibroblast co-culture induces M2 like macrophages that influence therapeutic response in a 3D model. PLOS ONE 12, e0182039 (2017).
[30]. LaRue, M. M. et al. Metabolic reprogramming of tumor-associated macrophages by collagen turnover promotes fibrosis in pancreatic cancer. Proc. Natl. Acad. Sci. 119, e2119168119 (2022).
[31]. Kemp, S. B. et al. Apolipoprotein E Promotes Immune Suppression in Pancreatic Cancer through NF-κB–Mediated Production of CXCL1. Cancer Res. 81, 4305–4318 (2021).
[32]. Kemp, S. B. et al. Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages. Life Sci. Alliance 4, e202000935 (2021).
[33]. Padoan, A., Plebani, M. & Basso, D. Inflammation and Pancreatic Cancer: Focus on Metabolism, Cytokines, and Immunity. Int. J. Mol. Sci. 20, 676 (2019).
[34]. Lee, B. Y. et al. Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis. Nat. Commun. 12, 7336 (2021).
[35]. Lankadasari, M. B., Mukhopadhyay, P., Mohammed, S. & Harikumar, K. B. TAMing pancreatic cancer: combat with a double edged sword. Mol. Cancer 18, 48 (2019).
[36]. Yang, Y. et al. M2 Macrophage-Derived Exosomes Promote Angiogenesis and Growth of Pancreatic Ductal Adenocarcinoma by Targeting E2F2. Mol. Ther. 29, 1226–1238 (2021).
[37]. Gross, A. et al. Technologies for Single-Cell Isolation. Int. J. Mol. Sci. 16, 16897–16919 (2015).
[38]. Nasir, I. et al. Tumor macrophage functional heterogeneity can inform the development of novel cancer therapies. Trends Immunol. 44, 971–985 (2023).
[39]. Yang, K., Yang, T., Yu, J., Li, F. & Zhao, X. Integrated transcriptional analysis reveals macrophage heterogeneity and macrophage-tumor cell interactions in the progression of pancreatic ductal adenocarcinoma. BMC Cancer 23, 199 (2023).
[40]. Marx, V. Method of the Year: spatially resolved transcriptomics. Nat. Methods 18, 9–14 (2021).
[41]. Gerlinger, M. et al. Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. N. Engl. J. Med. 366, 883–892 (2012).
[42]. Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic Cancer (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE155698)
[43]. Pancreatic Cancer with Xenium Human Multi-Tissue and Cancer Panel (https://www.10xgenomics.com/datasets/pancreatic-cancer-with-xenium-human-multi-tissue-and-cancer-panel-1-standard)
Cite this article
Li,M. (2025). Spatiotemporal Transcriptomic Dissection of Tumor-Associated Macrophage Heterogeneity and Dual-Function Molecular Nodes in Pancreatic Ductal Adenocarcinoma. Theoretical and Natural Science,113,61-83.
Data availability
The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.
Disclaimer/Publisher's Note
The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of EWA Publishing and/or the editor(s). EWA Publishing and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
About volume
Volume title: Proceedings of ICBioMed 2025 Symposium: AI for Healthcare: Advanced Medical Data Analytics and Smart Rehabilitation
© 2024 by the author(s). Licensee EWA Publishing, Oxford, UK. This article is an open access article distributed under the terms and
conditions of the Creative Commons Attribution (CC BY) license. Authors who
publish this series agree to the following terms:
1. Authors retain copyright and grant the series right of first publication with the work simultaneously licensed under a Creative Commons
Attribution License that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this
series.
2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the series's published
version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial
publication in this series.
3. Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and
during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See
Open access policy for details).
References
[1]. Chouari, T. et al. Advances in Immunotherapeutics in Pancreatic Ductal Adenocarcinoma. Cancers 15, 4265 (2023).
[2]. Ilic, M. & Ilic, I. Epidemiology of pancreatic cancer. World J. Gastroenterol. 22, 9694 (2016).
[3]. Klein, A. P. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat. Rev. Gastroenterol. Hepatol. 18, 493–502 (2021).
[4]. Ho, T. T. B. et al. Combination of gemcitabine and anti-PD-1 antibody enhances the anticancer effect of M1 macrophages and the Th1 response in a murine model of pancreatic cancer liver metastasis. J. Immunother. Cancer 8, e001367 (2020).
[5]. Zhu, Y. et al. CSF1/CSF1R Blockade Reprograms Tumor-Infiltrating Macrophages and Improves Response to T-cell Checkpoint Immunotherapy in Pancreatic Cancer Models. Cancer Res. 74, 5057–5069 (2014).
[6]. Locati, M., Curtale, G. & Mantovani, A. Diversity, Mechanisms, and Significance of Macrophage Plasticity. Annu. Rev. Pathol. Mech. Dis. 15, 123–147 (2020).
[7]. Wynn, T. A., Chawla, A. & Pollard, J. W. Macrophage biology in development, homeostasis and disease. Nature 496, 445–455 (2013).
[8]. Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).
[9]. Wu, Y. et al. Macrophage cell membrane-based nanoparticles: a new promising biomimetic platform for targeted delivery and treatment. J. Nanobiotechnology 20, 542 (2022).
[10]. Cai, H., Zhang, Y., Wang, J. & Gu, J. Defects in Macrophage Reprogramming in Cancer Therapy: The Negative Impact of PD-L1/PD-1. Front. Immunol. 12, 690869 (2021).
[11]. Ruffell, B. & Coussens, L. M. Macrophages and Therapeutic Resistance in Cancer. Cancer Cell 27, 462–472 (2015).
[12]. DeNardo, D. G. & Ruffell, B. Macrophages as regulators of tumour immunity and immunotherapy. Nat. Rev. Immunol. 19, 369–382 (2019).
[13]. Ngambenjawong, C., Gustafson, H. H. & Pun, S. H. Progress in tumor-associated macrophage (TAM)-targeted therapeutics. Adv. Drug Deliv. Rev. 114, 206–221 (2017).
[14]. Dai, E. et al. Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein. Autophagy 16, 2069–2083 (2020).
[15]. Mehla, K. & Singh, P. K. Metabolic Regulation of Macrophage Polarization in Cancer. Trends Cancer 5, 822–834 (2019).
[16]. Fendl, B., Berghoff, A. S., Preusser, M. & Maier, B. Macrophage and monocyte subsets as new therapeutic targets in cancer immunotherapy. ESMO Open 8, 100776 (2023).
[17]. Wei, C. et al. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol. Cancer 18, 64 (2019).
[18]. Wu, K. et al. Redefining Tumor-Associated Macrophage Subpopulations and Functions in the Tumor Microenvironment. Front. Immunol. 11, 1731 (2020).
[19]. Seyfried, T. N. & Huysentruyt, L. C. On the Origin of Cancer Metastasis. Crit. Rev. Oncog. 18, 43–73 (2013).
[20]. Cao, L., Meng, X., Zhang, Z., Liu, Z. & He, Y. Macrophage heterogeneity and its interactions with stromal cells in tumour microenvironment. Cell Biosci. 14, 16 (2024).
[21]. Zhang, X., Ji, L. & Li, M. O. Control of tumor-associated macrophage responses by nutrient acquisition and metabolism. Immunity 56, 14–31 (2023).
[22]. Zhang, X., Ji, L. & Li, M. O. Control of tumor-associated macrophage responses by nutrient acquisition and metabolism. Immunity 56, 14–31 (2023).
[23]. Gao, J., Liang, Y. & Wang, L. Shaping Polarization Of Tumor-Associated Macrophages In Cancer Immunotherapy. Front. Immunol. 13, 888713 (2022).
[24]. Mills, C. D., Lenz, L. L. & Harris, R. A. A Breakthrough: Macrophage-Directed Cancer Immunotherapy. Cancer Res. 76, 513–516 (2016).
[25]. Wang, H., Yung, M. M. H., Ngan, H. Y. S., Chan, K. K. L. & Chan, D. W. The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression. Int. J. Mol. Sci. 22, 6560 (2021).
[26]. Li, M. et al. Metabolism, metabolites, and macrophages in cancer. J. Hematol. Oncol.J Hematol Oncol 16, 80 (2023).
[27]. Halbrook, C. J. et al. Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer. Cell Metab. 29, 1390-1399.e6 (2019).
[28]. Menjivar, R. E. et al. Arginase 1 is a key driver of immune suppression in pancreatic cancer. eLife 12, e80721 (2023).
[29]. Kuen, J., Darowski, D., Kluge, T. & Majety, M. Pancreatic cancer cell/fibroblast co-culture induces M2 like macrophages that influence therapeutic response in a 3D model. PLOS ONE 12, e0182039 (2017).
[30]. LaRue, M. M. et al. Metabolic reprogramming of tumor-associated macrophages by collagen turnover promotes fibrosis in pancreatic cancer. Proc. Natl. Acad. Sci. 119, e2119168119 (2022).
[31]. Kemp, S. B. et al. Apolipoprotein E Promotes Immune Suppression in Pancreatic Cancer through NF-κB–Mediated Production of CXCL1. Cancer Res. 81, 4305–4318 (2021).
[32]. Kemp, S. B. et al. Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages. Life Sci. Alliance 4, e202000935 (2021).
[33]. Padoan, A., Plebani, M. & Basso, D. Inflammation and Pancreatic Cancer: Focus on Metabolism, Cytokines, and Immunity. Int. J. Mol. Sci. 20, 676 (2019).
[34]. Lee, B. Y. et al. Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis. Nat. Commun. 12, 7336 (2021).
[35]. Lankadasari, M. B., Mukhopadhyay, P., Mohammed, S. & Harikumar, K. B. TAMing pancreatic cancer: combat with a double edged sword. Mol. Cancer 18, 48 (2019).
[36]. Yang, Y. et al. M2 Macrophage-Derived Exosomes Promote Angiogenesis and Growth of Pancreatic Ductal Adenocarcinoma by Targeting E2F2. Mol. Ther. 29, 1226–1238 (2021).
[37]. Gross, A. et al. Technologies for Single-Cell Isolation. Int. J. Mol. Sci. 16, 16897–16919 (2015).
[38]. Nasir, I. et al. Tumor macrophage functional heterogeneity can inform the development of novel cancer therapies. Trends Immunol. 44, 971–985 (2023).
[39]. Yang, K., Yang, T., Yu, J., Li, F. & Zhao, X. Integrated transcriptional analysis reveals macrophage heterogeneity and macrophage-tumor cell interactions in the progression of pancreatic ductal adenocarcinoma. BMC Cancer 23, 199 (2023).
[40]. Marx, V. Method of the Year: spatially resolved transcriptomics. Nat. Methods 18, 9–14 (2021).
[41]. Gerlinger, M. et al. Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. N. Engl. J. Med. 366, 883–892 (2012).
[42]. Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic Cancer (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE155698)
[43]. Pancreatic Cancer with Xenium Human Multi-Tissue and Cancer Panel (https://www.10xgenomics.com/datasets/pancreatic-cancer-with-xenium-human-multi-tissue-and-cancer-panel-1-standard)