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This study presents a microparticle\u2010based traction force microscopy strategy for in situ quantification of compressive forces within 3D tumor spheroids. Multicellular spheroids composed of tumor cells (T), fibroblasts (F), and macrophages (M) were generated to mimic the tumor microenvironment and to understand the contribution of fibroblast\u2013macrophage crosstalk in tumor mechanobiology. Tri\u2010culture spheroids exhibited the highest proliferative capacity compared to mono\u2010 and bi\u2010cultured tumor spheroids. Gene expression profiling indicated strong fibroblast activation, extracellular matrix remodeling, and M2\u2010like macrophage polarization, highlighting a pro\u2010tumoral phenotype. Incorporation of deformable hydrogel microparticles allowed direct mapping of local compressive and indirect quantification of anisotropic stresses. This mapping revealed fibroblasts are the principal source of force generation with the spheroids. Notably, macrophages amplified bulk and anisotropic stresses over two\u2010fold through paracrine activation of fibroblasts. Spatial mapping showed pressure gradients from the core to the periphery, while temporal analyses demonstrated a progressive increase in mechanical stresses with spheroid growth. Together, these findings reveal a surprising governing of intratumoral mechanics by macrophage\u2013fibroblast interactions and demonstrate the potential of microparticle\u2010based 3D force mapping within complex tumor environments.<\/jats:p>","DOI":"10.1002\/adhm.71844","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:15:07Z","timestamp":1792156507000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Macrophage\u2013Fibroblast Crosstalk Governs Tumor Mechanics, as Revealed by Spatiotemporal Force Mapping in 3D Spheroids"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7134-1721","authenticated-orcid":false,"given":"Kunal P.","family":"Pednekar","sequence":"first","affiliation":[{"name":"Department of Medical Biosciences Radboud University Medical Centre  Nijmegen the Netherlands"},{"name":"Department of Bioengineering Technologies University of Twente  Enschede the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7800-4023","authenticated-orcid":false,"given":"Daan","family":"Vorselen","sequence":"additional","affiliation":[{"name":"Department of Cell Biology &amp; Immunology (CBI) Wageningen University &amp; Research  Wageningen the Netherlands"},{"name":"Center for Translational Immunology University Medical Center Utrecht and Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1050-650X","authenticated-orcid":false,"given":"Jai","family":"Prakash","sequence":"additional","affiliation":[{"name":"Department of Medical Biosciences Radboud University Medical Centre  Nijmegen the Netherlands"},{"name":"Department of Bioengineering Technologies University of Twente  Enschede the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,16]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2021.05.011"},{"key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"3043","DOI":"10.1016\/j.bbamcr.2015.05.007","article-title":"A Guide to Mechanobiology: Where Biology and Physics Meet","volume":"1853","author":"Jansen K. 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