Engineering macrophages for cancer immunotherapy: emerging insights and therapeutic potential

Engineering macrophages for cancer immunotherapy: emerging insights and therapeutic potential

  • Park, M. D., Silvin, A., Ginhoux, F. & Merad, M. Macrophages in health and disease. Cell 185, 4259–4279 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Italiani, P. & Boraschi, D. From monocytes to M1/M2 macrophages: phenotypical vs. functional differentiation. Front. Immunol. 5, 514 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Guilliams, M., Mildner, A. & Yona, S. Developmental and functional heterogeneity of monocytes. Immunity 49, 595–613 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Sommerfeld, S. D. et al. Interleukin-36gamma-producing macrophages drive IL-17-mediated fibrosis. Sci. Immunol. 4, https://doi.org/10.1126/sciimmunol.aax4783 (2019).

  • Martin, K. E. & Garcia, A. J. Macrophage phenotypes in tissue repair and the foreign body response: Implications for biomaterial-based regenerative medicine strategies. Acta Biomater. 133, 4–16 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med 19, 1423–1437 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kersten, K. et al. Spatiotemporal co-dependency between macrophages and exhausted CD8(+) T cells in cancer. Cancer Cell 40, 624–638.e629 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tylek, T., Wong, J., Vaughan, A. E. & Spiller, K. L. Biomaterial-mediated intracellular control of macrophages for cell therapy in pro-inflammatory and pro-fibrotic conditions. Biomaterials 308, 122545 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Meli, V. S. et al. Biophysical regulation of macrophages in health and disease. J. Leukoc. Biol. 106, 283–299 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Butenko, S. et al. Hydrogel crosslinking modulates macrophages, fibroblasts, and their communication, during wound healing. Nat. Commun. 15, 6820 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chung, L., Maestas, D. R. Jr, Housseau, F. & Elisseeff, J. H. Key players in the immune response to biomaterial scaffolds for regenerative medicine. Adv. Drug Deliv. Rev. 114, 184–192 (2017).

    Article 
    PubMed 

    Google Scholar
     

  • Witherel, C. E., Abebayehu, D., Barker, T. H. & Spiller, K. L. Macrophage and fibroblast interactions in biomaterial-mediated fibrosis. Adv. Health. Mater. 8, e1801451 (2019).

    Article 

    Google Scholar
     

  • Zarif, J. C. et al. Mannose receptor-positive macrophage infiltration correlates with prostate cancer onset and metastatic castration-resistant disease. Eur. Urol. Oncol. 2, 429–436 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Jaynes, J. M. et al. Mannose receptor (CD206) activation in tumor-associated macrophages enhances adaptive and innate antitumor immune responses. Sci. Transl. Med. 12, https://doi.org/10.1126/scitranslmed.aax6337 (2020).

  • Ma, R. Y., Black, A. & Qian, B. Z. Macrophage diversity in cancer revisited in the era of single-cell omics. Trends Immunol. 43, 546–563 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Strizova, Z. et al. M1/M2 macrophages and their overlaps – myth or reality? Clin. Sci. (Lond.) 137, 1067–1093 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Adebowale, K. G., Guerriero, J L. & Mitragotri, S. Dynamics of macrophage tumor infiltration. Appl. Phys. Rev. 10, https://doi.org/10.1063/5.0160924 (2023).

  • Guerriero, J. L. Macrophages: the road less traveled, changing anticancer therapy. Trends Mol. Med 24, 472–489 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mulder, K. et al. Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease. Immunity 54, 1883–1900.e1885 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Ray, A. et al. Targeting CD206+ macrophages disrupts the establishment of a key antitumor immune axis. J. Exp. Med. 222, https://doi.org/10.1084/jem.20240957 (2025).

  • Cavnar, M. J. et al. Tumor-associated macrophage infiltration in colorectal cancer liver metastases is associated with better outcome. Ann. Surg. Oncol. 24, 1835–1842 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhong, C. et al. PSGL-1 is a phagocytosis checkpoint that enables tumor escape from macrophage clearance. Sci. Immunol. 10, eadn4302 (2025).

    Article 
    PubMed 

    Google Scholar
     

  • Matusiak, M. et al. Spatially segregated macrophage populations predict distinct outcomes in colon cancer. Cancer Discov. 14, 1418–1439 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, M. et al. Spatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma. Nat. Commun. 15, 2113 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Enfield, K. S. S. et al. Spatial architecture of myeloid and T cells orchestrates immune evasion and clinical outcome in lung cancer. Cancer Discov. 14, 1018–1047 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Paterson, N. & Lammermann, T. Macrophage network dynamics depend on haptokinesis for optimal local surveillance. Elife 11, https://doi.org/10.7554/eLife.75354 (2022).

  • Mantovani, A., Allavena, P., Marchesi, F. & Garlanda, C. Macrophages as tools and targets in cancer therapy. Nat. Rev. Drug Discov. 21, 799–820 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Toledo, B. et al. Deciphering the performance of macrophages in tumour microenvironment: a call for precision immunotherapy. J. Hematol. Oncol. 17, 44 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kloosterman, D. J. & Akkari, L. Macrophages at the interface of the co-evolving cancer ecosystem. Cell 186, 1627–1651 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Cockram, T. O. J., Dundee, J. M., Popescu, A. S. & Brown, G. C. The phagocytic code regulating phagocytosis of mammalian cells. Front. Immunol. 12, 629979 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dolasia, K., Bisht, M. K., Pradhan, G., Udgata, A. & Mukhopadhyay, S. TLRs/NLRs: shaping the landscape of host immunity. Int Rev. Immunol. 37, 3–19 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Kelley, S. M. & Ravichandran, K. S. Putting the brakes on phagocytosis: “don’t-eat-me” signaling in physiology and disease. Embo Rep. 22, e52564 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ding, X. et al. Engineering macrophages via nanotechnology and genetic manipulation for cancer therapy. Front. Oncol. 11, 786913 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Du, H. et al. Tuning immunity through tissue mechanotransduction. Nat. Rev. Immunol. 23, 174–188 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Zhang, X. et al. Unraveling the mechanobiology of immune cells. Curr. Opin. Biotechnol. 66, 236–245 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, Z. et al. Viscoelastic synthetic antigen-presenting cells for augmenting the potency of cancer therapies. Nat. Biomed. Eng. 8, 1615–1633 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Adu-Berchie, K. et al. Generation of functionally distinct T-cell populations by altering the viscoelasticity of their extracellular matrix. Nat. Biomed. Eng. 7, 1374–1391 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vining, K. H. et al. Mechanical checkpoint regulates monocyte differentiation in fibrotic niches. Nat. Mater. 21, 939–950 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Alraies, Z. et al. Cell shape sensing licenses dendritic cells for homeostatic migration to lymph nodes. Nat. Immunol. 25, 1193–1206 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Settle, A. H. et al. beta2 integrins impose a mechanical checkpoint on macrophage phagocytosis. Nat. Commun. 15, 8182 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tello-Lafoz, M. et al. Cytotoxic lymphocytes target characteristic biophysical vulnerabilities in cancer. Immunity 54, 1037–1054.e1037 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Basu, R. et al. Cytotoxic T cells use mechanical force to potentiate target cell killing. Cell 165, 100–110 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huse, M. Mechanical forces in the immune system. Nat. Rev. Immunol. 17, 679–690 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lei, K. et al. Cancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy. Nat. Biomed. Eng. 5, 1411–1425 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhu, C., Chen, W., Lou, J., Rittase, W. & Li, K. Mechanosensing through immunoreceptors. Nat. Immunol. 20, 1269–1278 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, K. et al. Mechanical force regulates ligand binding and function of PD-1. Nat. Commun. 15, 8339 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Choi, H. K. et al. Mechanotransduction governs CD40 function and underlies X-linked Hyper IgM syndrome. Preprint at https://doi.org/10.1101/2023.07.23.550231 (2023).

  • Zhong, Z. et al. Human immune organoids to decode B cell response in healthy donors and patients with lymphoma. Nat. Mater. 24, 297–311 (2025).

    Article 
    PubMed 

    Google Scholar
     

  • Assen, F. P. et al. Multitier mechanics control stromal adaptations in the swelling lymph node. Nat. Immunol. 23, 1246–1255 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Horsnell, H. L. et al. Lymph node homeostasis and adaptation to immune challenge resolved by fibroblast network mechanics. Nat. Immunol. 23, 1169–1182 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Narain, R., Muncie-Vasic, J. M. & Weaver, V. M. Forcing the code: tension modulates signaling to drive morphogenesis and malignancy. Genes Dev. 39, 163–181 (2025).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tharp, K. M. et al. Tumor-associated macrophages restrict CD8(+) T cell function through collagen deposition and metabolic reprogramming of the breast cancer microenvironment. Nat. Cancer 5, 1045–1062 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jeffreys, N., Brockman, J. M., Zhai, Y., Ingber, D. E. & Mooney, D. J. Mechanical forces amplify TCR mechanotransduction in T cell activation and function. Appl. Phys. Rev. 11, 011304 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ma, S. et al. A role of PIEZO1 in iron metabolism in mice and humans. Cell 184, 969–982.e913 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Reis-Rodrigues, P. et al. Migrating immune cells globally coordinate protrusive forces. Nat. Immunol. 26, 1258–1266 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fritzsche, M. & Kruse, K. Mechanical force matters in early T cell activation. Proc. Natl. Acad. Sci. USA 121, e2404748121 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dustin, M. L. & Kam, L. C. Tapping out a mechanical code for T cell triggering. J. Cell Biol. 213, 501–503 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, J. et al. Osr2 functions as a biomechanical checkpoint to aggravate CD8(+) T cell exhaustion in tumor. Cell 187, 3409–3426.e3424 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Meizlish, M. L. et al. Mechanosensing regulates tissue repair program in macrophages. Sci. Adv. 10, eadk6906 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lewis, J. S. et al. The effect of cyclic mechanical strain on activation of dendritic cells cultured on adhesive substrates. Biomaterials 34, 9063–9070 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Golo, M., Newman, P. L. H., Kempe, D. & Biro, M. Mechanoimmunology in the solid tumor microenvironment. Biochem Soc. Trans. 52, 1489–1502 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Jain, N., Lord, J. M. & Vogel, V. Mechanoimmunology: Are inflammatory epigenetic states of macrophages tuned by biophysical factors? APL Bioeng. 6, 031502 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhao, L., Gui, Y. & Deng, X. Focus on mechano-immunology: new direction in cancer treatment. Int J. Surg. 111, 2590–2602 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, Z. et al. Gut mechanoimmunology: shaping immune response through physical cues. Phys. Life Rev. 50, 13–26 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Pageon, S. V., Govendir, M. A., Kempe, D. & Biro, M. Mechanoimmunology: molecular-scale forces govern immune cell functions. Mol. Biol. Cell 29, 1919–1926 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • He, Y. et al. Nanoscale acoustic oscillator for mechanoimmunology: NAOMI. Sci. Adv. 11, eadx3851 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mukhopadhyay, M. Immunomechanics. Nat. Methods 20, 35 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Janssen, E., van den Dries, K., Ventre, M. & Cambi, A. Mechanobiology of myeloid cells. Curr. Opin. Cell Biol. 86, 102311 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Lee, M., Du, H., Winer, D. A., Clemente-Casares, X. & Tsai, S. Mechanosensing in macrophages and dendritic cells in steady-state and disease. Front. Cell Dev. Biol. 10, 1044729 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hong, J. et al. A TCR mechanotransduction signaling loop induces negative selection in the thymus. Nat. Immunol. 19, 1379–1390 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Comrie, W. A., Babich, A. & Burkhardt, J. K. F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse. J. Cell Biol. 208, 475–491 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Luo, B. H., Carman, C. V. & Springer, T. A. Structural basis of integrin regulation and signaling. Annu. Rev. Immunol. 25, 619–647 (2007).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Choi, H. K. & Zhu, C. Catch bonds in immunology. Annu. Rev. Immunol. 43, 641–666 (2025).

    Article 
    PubMed 

    Google Scholar
     

  • Ezzo, M. et al. Acute contact with profibrotic macrophages mechanically activates fibroblasts via alphavbeta3 integrin-mediated engagement of Piezo1. Sci. Adv. 10, eadp4726 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Atcha, H. et al. Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing. Nat. Commun. 12, 3256 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sreejit, G., Fleetwood, A. J., Murphy, A. J. & Nagareddy, P. R. Origins and diversity of macrophages in health and disease. Clin. Transl. Immunol. 9, e1222 (2020).

    Article 

    Google Scholar
     

  • Ni, Y. et al. Macrophages modulate stiffness-related foreign body responses through plasma membrane deformation. Proc. Natl. Acad. Sci. USA 120, e2213837120 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ranade, S. S., Syeda, R. & Patapoutian, A. Mechanically activated ion channels. Neuron 87, 1162–1179 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, S. et al. Membrane curvature governs the distribution of Piezo1 in live cells. Nat. Commun. 13, 7467 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, J. et al. Piezo1: structural pharmacology and mechanotransduction mechanisms. Trends Pharm. Sci. 46, 752–770 (2025).

    Article 
    PubMed 

    Google Scholar
     

  • Solis, A. G. et al. Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity. Nature 573, 69–74 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, Y. et al. Stiffness sensing via Piezo1 enhances macrophage efferocytosis and promotes the resolution of liver fibrosis. Sci. Adv. 10, eadj3289 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, J. et al. Determining the Young’s modulus of the bacterial cell envelope. ACS Biomater. Sci. Eng. 10, 2956–2966 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Islamzada, E. et al. Red blood cells with reduced deformability are selectively cleared from circulation in a mouse model. Blood Adv. 9, 2988–2996 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sosale, N. G. et al. Cell rigidity and shape override CD47’s “self”-signaling in phagocytosis by hyperactivating myosin-II. Blood 125, 542–552 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Liu, Z. et al. Cancer cells display increased migration and deformability in pace with metastatic progression. Faseb J. 34, 9307–9315 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Joshi, H. et al. Mechanosensitivity of macrophage polarization: comparing small molecule leukadherin-1 to substrate stiffness. Front. Immunol. 16, 1420325 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Meli, V. S. et al. YAP-mediated mechanotransduction tunes the macrophage inflammatory response. Sci. Adv. 6, https://doi.org/10.1126/sciadv.abb8471 (2020).

  • Sridharan, R., Cavanagh, B., Cameron, A. R., Kelly, D. J. & O’Brien, F. J. Material stiffness influences the polarization state, function and migration mode of macrophages. Acta Biomater. 89, 47–59 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Mei, F. et al. Matrix stiffness regulates macrophage polarisation via the Piezo1-YAP signalling axis. Cell Prolif. 57, e13640 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Adlerz, K. M., Aranda-Espinoza, H. & Hayenga, H. N. Substrate elasticity regulates the behavior of human monocyte-derived macrophages. Eur. Biophys. 45, 301–309 (2016).

    Article 

    Google Scholar
     

  • Neupane, A. S. et al. Patrolling alveolar macrophages conceal bacteria from the immune system to maintain homeostasis. Cell 183, 110–125.e111 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Hu, J. et al. Microglial Piezo1 senses Abeta fibril stiffness to restrict Alzheimer’s disease. Neuron 111, 15–29.e18 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Dooling, L. J. et al. Cooperative phagocytosis of solid tumours by macrophages triggers durable anti-tumour responses. Nat. Biomed. Eng. 7, 1081–1096 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Morva, A., Arroyo, A. B., Andreeva, L., Tapia-Abellan, A. & Luengo-Gil, G. Unleashing the power of CAR-M therapy in solid tumors: a comprehensive review. Front. Immunol. 16, 1615760 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chao, M. P., Weissman, I. L. & Majeti, R. The CD47-SIRPalpha pathway in cancer immune evasion and potential therapeutic implications. Curr. Opin. Immunol. 24, 225–232 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tang, Z. et al. CD47 masks pro-phagocytic ligands in cis on tumor cells to suppress antitumor immunity. Nat. Immunol. 24, 2032–2041 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, H. et al. Silencing of SIRPalpha enhances the antitumor efficacy of CAR-M in solid tumors. Cell Mol. Immunol. 21, 1335–1349 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, Y. et al. Emerging phagocytosis checkpoints in cancer immunotherapy. Signal Transduct. Target Ther. 8, 104 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, H., Xun, Y. & You, H. The landscape overview of CD47-based immunotherapy for hematological malignancies. Biomark. Res. 11, 15 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jiang, C. et al. Targeting the CD47/SIRPalpha pathway in malignancies: recent progress, difficulties and future perspectives. Front. Oncol. 14, 1378647 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • ClinicalTrials.gov. CD47 Clinical Trials. https://clinicaltrials.gov/search?cond=cd47 (2025).

  • Muntjewerff, E. M., Meesters, L. D. & van den Bogaart, G. Antigen cross-presentation by macrophages. Front. Immunol. 11, 1276 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Arnold, C. E., Gordon, P., Barker, R. N. & Wilson, H. M. The activation status of human macrophages presenting antigen determines the efficiency of Th17 responses. Immunobiology 220, 10–19 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Silva, M. et al. A particulate saponin/TLR agonist vaccine adjuvant alters lymph flow and modulates adaptive immunity. Sci. Immunol. 6, eabf1152 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, H. et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature 507, 519–522 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Irvine, D. J., Aung, A. & Silva, M. Controlling timing and location in vaccines. Adv. Drug Deliv. Rev. 158, 91–115 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dash, S. P., Gupta, S. & Sarangi, P. P. Monocytes and macrophages: origin, homing, differentiation, and functionality during inflammation. Heliyon 10, e29686 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hoffmann, E. J. & Ponik, S. M. Biomechanical contributions to macrophage activation in the tumor microenvironment. Front. Oncol. 10, 787 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McNally, A. K. & Anderson, J. M. Beta1 and beta2 integrins mediate adhesion during macrophage fusion and multinucleated foreign body giant cell formation. Am. J. Pathol. 160, 621–630 (2002).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gui, P. et al. The protease-dependent mesenchymal migration of tumor-associated macrophages as a target in cancer immunotherapy. Cancer Immunol. Res 6, 1337–1351 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Friedl, P. & Wolf, K. Plasticity of cell migration: a multiscale tuning model. J. Cell Biol. 188, 11–19 (2010).

    Article 
    PubMed 

    Google Scholar
     

  • Friedl, P. & Wolf, K. Proteolytic and non-proteolytic migration of tumour cells and leucocytes. Biochem. Soc. Symp. 277–285. https://doi.org/10.1042/bss0700277 (2003).

  • Travnickova, J. et al. Macrophage morphological plasticity and migration is Rac signalling and MMP9 dependant. Sci. Rep. 11, 10123 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sanz-Moreno, V. Tumour invasion: a new twist on Rac-driven mesenchymal migration. Curr. Biol. 22, R449–R451 (2012).

    Article 
    PubMed 

    Google Scholar
     

  • Friedl, P. & Weigelin, B. Interstitial leukocyte migration and immune function. Nat. Immunol. 9, 960–969 (2008).

    Article 
    PubMed 

    Google Scholar
     

  • Adebowale, K. et al. Monocytes use protrusive forces to generate migration paths in viscoelastic collagen-based extracellular matrices. Proc. Natl. Acad. Sci. USA 122, e2309772122 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Argyle, D. & Kitamura, T. Targeting macrophage-recruiting chemokines as a novel therapeutic strategy to prevent the progression of solid tumors. Front. Immunol. 9, 2629 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 122, 787–795 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Son, B., Lee, W., Kim, H., Shin, H. & Park, H. H. Targeted therapy of cancer stem cells: inhibition of mTOR in pre-clinical and clinical research. Cell Death Dis. 15, 696 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Panwar, V. et al. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transduct. Target Ther. 8, 375 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, H. W., Choi, H. J., Ha, S. J., Lee, K. T. & Kwon, Y. G. Recruitment of monocytes/macrophages in different tumor microenvironments. Biochim. Biophys. Acta 1835, 170–179 (2013).

    PubMed 

    Google Scholar
     

  • Du, W. et al. High-motility pro-tumorigenic monocytes drive macrophage enrichment in the tumor microenvironment. Preprint at https://doi.org/10.1101/2024.07.16.603739 (2024).

  • Khurana, A. et al. Visualization of macrophage recruitment in head and neck carcinoma model using fluorine-19 magnetic resonance imaging. Magn. Reson Med 79, 1972–1980 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Yang, H. et al. Magnetic Resonance Imaging of Macrophage Response to Radiation Therapy. Cancers 15, https://doi.org/10.3390/cancers15245874 (2023).

  • Sugimoto, M. A., Sousa, L. P., Pinho, V., Perretti, M. & Teixeira, M. M. Resolution of inflammation: What Controls Its Onset? Front. Immunol. 7, 160 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Serhan, C. N. & Savill, J. Resolution of inflammation: the beginning programs the end. Nat. Immunol. 6, 1191–1197 (2005).

    Article 
    PubMed 

    Google Scholar
     

  • Zaveri, T. D., Lewis, J. S., Dolgova, N. V., Clare-Salzler, M. J. & Keselowsky, B. G. Integrin-directed modulation of macrophage responses to biomaterials. Biomaterials 35, 3504–3515 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zaveri, T. D. et al. Macrophage integrins modulate response to ultra-high molecular weight polyethylene particles and direct particle-induced osteolysis. Biomaterials 115, 128–140 (2017).

    Article 
    PubMed 

    Google Scholar
     

  • Haskill, S., Yurochko, A. D. & Isaacs, K. L. Regulation of macrophage infiltration and activation in sites of chronic inflammation. Ann. N. Y Acad. Sci. 664, 93–102 (1992).

    Article 
    PubMed 

    Google Scholar
     

  • McCarthy, J. B., Vachhani, B. V., Wahl, S. M., Finbloom, D. S. & Feldman, G. M. Human monocyte binding to fibronectin enhances IFN-gamma-induced early signaling events. J. Immunol. 159, 2424–2430 (1997).

    Article 
    PubMed 

    Google Scholar
     

  • Schmid, M. C. et al. Integrin CD11b activation drives anti-tumor innate immunity. Nat. Commun. 9, 5379 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Atcha, H. et al. Crosstalk between CD11b and Piezo1 mediates macrophage responses to mechanical cues. Front. Immunol. 12, 689397 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yao, M. et al. Force- and cell state-dependent recruitment of Piezo1 drives focal adhesion dynamics and calcium entry. Sci. Adv. 8, eabo1461 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lei, M. et al. Cell-cell and cell-matrix adhesion regulated by Piezo1 is critical for stiffness-dependent DRG neuron aggregation. Cell Rep. 42, 113522 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Wang, Y. et al. Macrophage-derived extracellular vesicles: diverse mediators of pathology and therapeutics in multiple diseases. Cell Death Dis. 11, 924 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kumar, M. A. et al. Extracellular vesicles as tools and targets in therapy for diseases. Signal Transduct. Target Ther. 9, 27 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cianciaruso, C. et al. Molecular profiling and functional analysis of macrophage-derived tumor extracellular vesicles. Cell Rep. 27, 3062–3080.e3011 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhou, J. et al. Exosomes released from tumor-associated macrophages transfer miRNAs that induce a Treg/Th17 cell imbalance in epithelial ovarian cancer. Cancer Immunol. Res. 6, 1578–1592 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Prestwich, R. J. et al. The immune system-is it relevant to cancer development, progression and treatment? Clin. Oncol. 20, 101–112 (2008).

    Article 

    Google Scholar
     

  • Virchow, R. Cellular pathology. As based upon physiological and pathological histology. Lecture XVI-Atheromatous affection of arteries. 1858. Nutr. Rev. 47, 23–25 (1989).

    Article 
    PubMed 

    Google Scholar
     

  • Zhang, Y. & Zhang, Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol. Immunol. 17, 807–821 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Coley, W. B. I. I. Contribution to the Knowledge of Sarcoma. Ann. Surg. 14, 199–220 (1891).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McCarthy, E. F. The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop. J. 26, 154–158 (2006).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Idos, G. E. et al. The prognostic implications of tumor infiltrating lymphocytes in colorectal cancer: a systematic review and meta-analysis. Sci. Rep. 10, 3360 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bida, M., Miya, T. V., Hull, R. & Dlamini, Z. Tumor-infiltrating lymphocytes in melanoma: from prognostic assessment to therapeutic applications. Front. Immunol. 15, 1497522 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ozcan, D. et al. Prognostic value of tumor-infiltrating lymphocytes in irradiated node-positive breast cancer patients. Breast 83, 104525 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Du, M., Cai, Y. M., Yin, Y. L., Xiao, L. & Ji, Y. Evaluating tumor-infiltrating lymphocytes in hepatocellular carcinoma using hematoxylin and eosin-stained tumor sections. World J. Clin. Cases 10, 856–869 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fidler, I. J. Therapy of cancer metastasis by systemic activation of macrophages. Adv. Pharm. 30, 271–326 (1994).

    Article 

    Google Scholar
     

  • Fidler, I. J. & Kleinerman, E. S. Therapy of cancer metastasis by systemic activation of macrophages: from the bench to the clinic. Res Immunol. 144, 284–287 (1993).

    Article 
    PubMed 

    Google Scholar
     

  • Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Canella, A. & Rajappa, P. Therapeutic utility of engineered myeloid cells in the tumor microenvironment. Cancer Gene Ther. 30, 964–972 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Clevenger, A. J., Jha, A., Moore, E. & Raghavan, S. A. Manipulating immune activity of macrophages: a materials and mechanics perspective. Trends Biotechnol. 43, 131–144 (2025).

    Article 
    PubMed 

    Google Scholar
     

  • Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pittet, M. J., Michielin, O. & Migliorini, D. Clinical relevance of tumour-associated macrophages. Nat. Rev. Clin. Oncol. 19, 402–421 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Hochstadt, J., Martinez Pacheco, S. & Casanova-Acebes, M. Embracing diversity: macrophage complexity in cancer. Trends Cancer 11, 351–364 (2025).

    Article 
    PubMed 

    Google Scholar
     

  • Brownlie, D. et al. Metastasis-associated macrophages constrain antitumor capability of natural killer cells in the metastatic site at least partially by membrane bound transforming growth factor beta. J. Immunother. Cancer 9, https://doi.org/10.1136/jitc-2020-001740 (2021).

  • Timperi, E. et al. Lipid-associated macrophages are induced by cancer-associated fibroblasts and mediate immune suppression in breast cancer. Cancer Res. 82, 3291–3306 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Guzman, G., Reed, M. R., Bielamowicz, K., Koss, B. & Rodriguez, A. CAR-T therapies in solid tumors: opportunities and challenges. Curr. Oncol. Rep. 25, 479–489 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Peng, L., Sferruzza, G., Yang, L., Zhou, L. & Chen, S. CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors. Cell Mol. Immunol. 21, 1089–1108 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yan, T., Zhu, L. & Chen, J. Current advances and challenges in CAR T-Cell therapy for solid tumors: tumor-associated antigens and the tumor microenvironment. Exp. Hematol. Oncol. 12, 14 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Anderson, N. R., Minutolo, N. G., Gill, S. & Klichinsky, M. Macrophage-based approaches for cancer immunotherapy. Cancer Res. 81, 1201–1208 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Lu, J. et al. CAR Macrophages: a promising novel immunotherapy for solid tumors and beyond. Biomark. Res. 12, 86 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Klichinsky, M. et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat. Biotechnol. 38, 947–953 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sunseri, N., O’Brien, M., Bhardwaj, N. & Landau, N. R. Human immunodeficiency virus type 1 modified to package Simian immunodeficiency virus Vpx efficiently infects macrophages and dendritic cells. J. Virol. 85, 6263–6274 (2011).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bobadilla, S., Sunseri, N. & Landau, N. R. Efficient transduction of myeloid cells by an HIV-1-derived lentiviral vector that packages the Vpx accessory protein. Gene Ther. 20, 514–520 (2013).

    Article 
    PubMed 

    Google Scholar
     

  • Reiss, K. A. et al. CAR-macrophage therapy for HER2-overexpressing advanced solid tumors: a phase 1 trial. Nat. Med. 31, 1171–1182 (2025).

    Article 
    PubMed 

    Google Scholar
     

  • Chen, Y. et al. CAR-macrophage: a new immunotherapy candidate against solid tumors. Biomed. Pharmacother. 139, 111605 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Morrissey, M. A. et al. Chimeric antigen receptors that trigger phagocytosis. Elife 7, https://doi.org/10.7554/eLife.36688 (2018).

  • Schlam, D. et al. Phosphoinositide 3-kinase enables phagocytosis of large particles by terminating actin assembly through Rac/Cdc42 GTPase-activating proteins. Nat. Commun. 6, 8623 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dooling, L. J. et al. Clustered macrophages cooperate to eliminate tumors via coordinated intrudopodia. Proc. Natl. Acad. Sci. USA 122, e2425452122 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, S. et al. CAR macrophages with built-In CD47 blocker combat tumor antigen heterogeneity and activate T cells via cross-presentation. Nat. Commun. 16, 4069 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Polak, R. et al. Liposome-loaded cell backpacks. Adv. Health. Mater. 4, 2832–2841 (2015).

    Article 

    Google Scholar
     

  • Xu, L., Zolotarskaya, O. Y., Yeudall, W. A. & Yang, H. Click hybridization of immune cells and polyamidoamine dendrimers. Adv. Health. Mater. 3, 1430–1438 (2014).

    Article 

    Google Scholar
     

  • Ayer, M. & Klok, H. A. Cell-mediated delivery of synthetic nano- and microparticles. J. Control Release 259, 92–104 (2017).

    Article 
    PubMed 

    Google Scholar
     

  • Shields, C. W. T. et al. Cellular backpacks for macrophage immunotherapy. Sci. Adv. 6, eaaz6579 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhao, Z. et al. Engineering of living cells with polyphenol-functionalized biologically active nanocomplexes. Adv. Mater. 32, e2003492 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Kwan, M. M. C. et al. Particle Shape Modulates the Function of Adoptive Macrophage Transfers. Adv. Healthc. Mater. e01348, https://doi.org/10.1002/adhm.202501348 (2025).

  • Rodell, C. B. et al. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat. Biomed. Eng. 2, 578–588 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Griffin, K. V., Saunders, M. N., Lyssiotis, C. A. & Shea, L. D. Engineering immunity using metabolically active polymeric nanoparticles. Trends Biotechnol. 43, 1371–1384 (2025).

    Article 
    PubMed 

    Google Scholar
     

  • Bender, E. C., Sircar, A. J., Taubenfeld, E. K. & Suggs, L. J. Modulating lipid-polymer nanoparticles’ physicochemical properties to alter macrophage uptake. ACS Biomater. Sci. Eng. 10, 2911–2924 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kraynak, C. A., Yan, D. J. & Suggs, L. J. Modulating inflammatory macrophages with an apoptotic body-inspired nanoparticle. Acta Biomater. 108, 250–260 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Li, S. et al. Nanomedicine engulfed by macrophages for targeted tumor therapy. Int. J. Nanomed. 11, 4107–4124 (2016).

    Article 

    Google Scholar
     

  • Nguyen, V. D. et al. Macrophage-mediated delivery of multifunctional nanotherapeutics for synergistic chemo-photothermal therapy of solid tumors. ACS Appl. Mater. Interfaces 12, 10130–10141 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Ramesh, A., Kumar, S., Nandi, D. & Kulkarni, A. CSF1R- and SHP2-inhibitor-loaded nanoparticles enhance cytotoxic activity and phagocytosis in tumor-associated macrophages. Adv. Mater. 31, e1904364 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Wesolowski, R. et al. Phase Ib study of the combination of pexidartinib (PLX3397), a CSF-1R inhibitor, and paclitaxel in patients with advanced solid tumors. Ther. Adv. Med Oncol. 11, 1758835919854238 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mitchell, M. J. & King, M. R. Leukocytes as carriers for targeted cancer drug delivery. Expert Opin. Drug Deliv. 12, 375–392 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Wang, L. L. et al. Preclinical characterization of macrophage-adhering gadolinium micropatches for MRI contrast after traumatic brain injury in pigs. Sci. Transl. Med. 16, eadk5413 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Lin, F., Luo, H., Wang, J., Li, Q. & Zha, L. Macrophage-derived extracellular vesicles as new players in chronic non-communicable diseases. Front. Immunol. 15, 1479330 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Zou, Y., Zhou, Y., Li, G., Dong, Y. & Hu, S. Clinical applications of extracellular vesicles: recent advances and emerging trends. Front. Bioeng. Biotechnol. 13, 1671963 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Anfray, C., Ummarino, A., Andon, F. T. & Allavena, P. Current strategies to target tumor-associated-macrophages to improve anti-tumor immune responses. Cells 9, https://doi.org/10.3390/cells9010046 (2019).

  • Sun, M. et al. Adoptive cell therapy with macrophage-drug conjugates facilitates cytotoxic drug transfer and immune activation in glioblastoma models. Sci. Transl. Med. 17, eadr4058 (2025).

    Article 
    PubMed 

    Google Scholar
     

  • Huang, W. et al. Clinical pharmacology perspectives for adoptive cell therapies in oncology. Clin. Pharm. Ther. 112, 968–981 (2022).

    Article 

    Google Scholar
     

  • Li, R., Grosskopf, A. K., Joslyn, L. R., Stefanich, E. G. & Shivva, V. Cellular kinetics and biodistribution of adoptive T cell therapies: from biological principles to effects on patient outcomes. AAPS J. 27, 55 (2025).

    Article 
    PubMed 

    Google Scholar
     

  • Veerasubramanian, P. K. et al. A Src-H3 acetylation signaling axis integrates macrophage mechanosensation with inflammatory response. Biomaterials 279, 121236 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jain, N., Moeller, J. & Vogel, V. Mechanobiology of macrophages: how physical factors coregulate macrophage plasticity and phagocytosis. Annu Rev. Biomed. Eng. 21, 267–297 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Sapudom, J. et al. 3D in vitro M2 macrophage model to mimic modulation of tissue repair. NPJ Regen. Med 6, 83 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Burchett, A., Siri, S., Li, J., Lu, X. & Datta, M. Novel 3-D macrophage spheroid model reveals reciprocal regulation of immunomechanical stress and mechano-immunological response. Cell Mol. Bioeng. 17, 329–344 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Burchett, A., Chen, H., Najera, J., Howard, S. & Datta, M. Chronic compression drives macrophages toward a pathological pro-tumor state. Preprint at https://doi.org/10.1101/2025.05.13.653793 (2025).

  • Liu, Y. & Segura, T. Biomaterials-mediated regulation of macrophage cell fate. Front. Bioeng. Biotechnol. 8, 609297 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Graf, J. et al. Macrophage variance: investigating how macrophage origin influences responses to soluble and physical cues with immortalized vs. primary cells in 2D and 3D culture. Front. Biomater. Sci. 3, https://doi.org/10.3389/fbiom.2024.1399448 (2024).

  • Guillot, A. & Tacke, F. Liver macrophages revisited: The expanding universe of versatile responses in a spatiotemporal context. Hepatol. Commun. 8, https://doi.org/10.1097/HC9.0000000000000491 (2024).

  • Stark, C. J S. E. N, M. T. -Omics approaches to study and model cell-cell interactions in engineered tissues. Front. Chem. Eng. 7, https://doi.org/10.3389/fceng.2025.1629455.

  • Ma, C. et al. Bioengineered immunocompetent preclinical trial-on-chip tool enables screening of CAR T cell therapy for leukaemia. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-025-01428-2 (2025).

  • Knight, H. R. et al. Bioengineering approaches to trained immunity: Physiologic targets and therapeutic strategies. Elife 14, https://doi.org/10.7554/eLife.106339 (2025).

  • Xiang, Y. et al. Multifaceted cancer alleviation by cowpea mosaic virus in a bioprinted ovarian cancer peritoneal spheroid model. Biomaterials 311, 122663 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tang, M. et al. Integration of 3D bioprinting and multi-algorithm machine learning identified glioma susceptibilities and microenvironment characteristics. Cell Discov. 10, 39 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Staros, R. et al. Perspectives for 3D-bioprinting in modeling of tumor immune evasion. Cancers 14, https://doi.org/10.3390/cancers14133126 (2022).

  • Wang, X., Luo, Y., Ma, Y., Wang, P. & Yao, R. Converging bioprinting and organoids to better recapitulate the tumor microenvironment. Trends Biotechnol. 42, 648–663 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Jung, M., Ghamrawi, S., Du, E. Y., Gooding, J. J. & Kavallaris, M. Advances in 3D bioprinting for cancer biology and precision medicine: from matrix design to application. Adv. Health. Mater. 11, e2200690 (2022).

    Article 

    Google Scholar
     

  • Li, Y. C, H.; Cui, H. Precision Spatial Control of Tumor-Stroma Interactions in Cancer Models via 3D Bioprinting for Advanced Research and Therapy. Adv. Funct. Mater. https://doi.org/10.1002/adfm.202503391 (2025).

  • Datta, P., Dey, M., Ataie, Z., Unutmaz, D. & Ozbolat, I. T. 3D bioprinting for reconstituting the cancer microenvironment. NPJ Precis Oncol. 4, 18 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, Z., Chen, X., Gao, S., Fang, X. & Ren, S. 3D bioprinted tumor model: a prompt and convenient platform for overcoming immunotherapy resistance by recapitulating the tumor microenvironment. Cell Oncol. 47, 1113–1126 (2024).

    Article 

    Google Scholar
     

  • Visalakshan, R. M. et al. Opportunities and challenges to engineer 3D models of tumor-adaptive immune interactions. Front. Immunol. 14, 1162905 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mu, P. et al. Newly developed 3D in vitro models to study tumor-immune interaction. J. Exp. Clin. Cancer Res. 42, 81 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ahmed, T. Biomaterial-based in vitro 3D modeling of glioblastoma multiforme. Cancer Pathog. Ther. 1, 177–194 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huang, M. S. C, F.; Roth, J. G., Heilshorn, S. C. Organoid bioprinting: from cells to functional tissues. Nat. Rev. Bioeng. https://doi.org/10.1038/s44222-024-00268-0 (2024).

  • Zhang, D., Huerta-Lopez, C. & Heilshorn, S. C. Organoid bioprinting to pattern the matrix microenvironment. Curr. Opin. Biomed. Eng. 35, https://doi.org/10.1016/j.cobme.2025.100607 (2025).

  • Hanif, F., Muzaffar, K., Perveen, K., Malhi, S. M. & Simjee Sh, U. Glioblastoma multiforme: a review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac. J. Cancer Prev. 18, 3–9 (2017).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pierini, S. et al. Chimeric antigen receptor macrophages (CAR-M) sensitize HER2+ solid tumors to PD1 blockade in pre-clinical models. Nat. Commun. 16, 706 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bhatia, D., Dolcetti, R. & Mazzieri, R. Are monocytes a preferable option to develop myeloid cell-based therapies for solid tumors? J. Exp. Clin. Cancer Res 44, 98 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Billingsley, M. M. et al. In vivo mRNA CAR T cell engineering via targeted ionizable lipid nanoparticles with extrahepatic tropism. Small 20, e2304378 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Yang, S. et al. Advances in engineered macrophages: a new frontier in cancer immunotherapy. Cell Death Dis. 15, 238 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Na, Y. R., Kim, S. W. & Seok, S. H. A new era of macrophage-based cell therapy. Exp. Mol. Med. 55, 1945–1954 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar