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We previously showed that inhibiting the colony-stimulating factor-1 receptor (CSF1R) pathway in monocytes and macrophages can block the FBR to implanted materials. Here, we demonstrate that coencapsulation of slow-releasing CSF1R inhibitor (GW2580) crystals with human stem cell\u2013derived \u03b2 cells (SC-\u03b2) in alginate spheres enables stable glycemic control for 1 year in immune-competent diabetic C57BL\/6 mice. In nonhuman primates (NHPs), GW2580 crystals similarly protected viable, glucose-responsive allogeneic \u03b2 cells for 1 month without systemic immune suppression. In contrast, the same xenogeneic human SC-\u03b2 cell formulation that functioned long-term in mice elicited extensive sphere overgrowth and graft failure in NHPs. Serum cytokine profiling and transcriptomic analysis of omental biopsies at day 30 revealed pronounced adaptive immune activation in xenogeneic recipients, including enrichment of CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, CD19\n                    <jats:sup>+<\/jats:sup>\n                    B cells, and antigen-presenting cell programs marked by elevated MHC class II expression. Chemokines\n                    <jats:italic toggle=\"yes\">CCL17<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">CCL22<\/jats:italic>\n                    , and\n                    <jats:italic toggle=\"yes\">CXCL13<\/jats:italic>\n                    were among the most highly up-regulated transcripts, mirroring responses observed previously with profibrotic alginate formulations without cells. These findings underscore the issues associated with xenogeneic cell sources in higher-order species yet indicate that targeting innate immune pathways with localized CSF1R inhibition may be sufficient to enable function of encapsulated allogeneic cell therapies.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adt1055","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T18:58:25Z","timestamp":1769626705000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Crystallized colony-stimulating factor-1 receptor inhibitor protects immunoisolated allo but not xeno transplants in primates"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5283-7388","authenticated-orcid":true,"given":"Matthew A.","family":"Bochenek","sequence":"first","affiliation":[{"name":"David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA."},{"name":"Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA."},{"name":"Department of Anesthesiology, Boston Children\u2019s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9801-5301","authenticated-orcid":true,"given":"Shady","family":"Farah","sequence":"additional","affiliation":[{"name":"David H. 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