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The C\u2010type lectin CLEC10A (MGL\/CD301) recognises a single terminal \u03b1\u2010N\u2010acetylgalactosamine (\u03b1\u2010GalNAc) and couples this minimalist glycan cue to context\u2010dependent inflammatory or reparative programmes, making it an attractive target for precision macrophage re\u2010programming. This review synthesises mechanistic, pre\u2010clinical and clinical data on Gc protein\u2010derived macrophage\u2010activating factor 2.0 (GcMAF2.0), a mono\u2010\u03b1\u2010GalNAc derivative of vitamin\u2010D\u2010binding protein that engages CLEC10A with high avidity. We summarise lessons from heterogeneous \u201cGcMAF1.0\u201d products, outline GMP workflows that yield EF\u2010M1\/EF\u2010M2, and review CLEC10A\u2010centred signalling and metabolic re\u2010wiring, including SYK versus STAT6\/PPAR\u03b3 cascades and shifts in arginine, glucose and fatty\u2010acid metabolism. Cross\u2010species data from rodent inflammation models, human and canine myeloid cells, barrier\u2010tissue and tumour models, and mesoscopic platforms indicate that \u03b1\u2010GalNAc ligands and EF\u2010M2 bias macrophage profiles and attenuate joint and barrier\u2010tissue inflammation. A randomised double\u2010blind placebo\u2010controlled trial of EF\u2010M2 in canine osteoarthritis links macrophage repolarisation to pain relief, gait restoration and serum ARG1\/iNOS and IL\u201010\/TNF\u2010\u03b1 shifts, providing disease\u2010modifying proof of concept. We also review the small, uncontrolled human experience with analytically characterised GcMAF2.0 (\u2248120 patient\u2010courses), noting favourable short\u2010term tolerability but low certainty of benefit and a need for randomised, lot\u2010traceable trials with mechanistic endpoints. Overall, we position the \u03b1\u2010GalNAc\u2013CLEC10A axis as a tunable handle on macrophage plasticity and outline the experimental and regulatory priorities needed to translate GcMAF2.0 into evidence\u2010based immunotherapy.<\/jats:p>","DOI":"10.1111\/imm.70132","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T14:51:28Z","timestamp":1773931888000},"page":"561-581","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Precision Glyco\u2010Modulated\n                    <scp>GcMAF2.0<\/scp>\n                    Targets\n                    <scp>CLEC10A<\/scp>\n                    to Bidirectionally Re\u2010Wire Macrophage States: Cross\u2010Species Evidence, Mechanistic Omics and Translational Horizons"],"prefix":"10.1111","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9494-4234","authenticated-orcid":false,"given":"Evgeny","family":"Pokushalov","sequence":"first","affiliation":[{"name":"Scientific Research Laboratory, Triangel Scientific  San Francisco California USA"},{"name":"Center for New Medical Technologies  Novosibirsk Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry","family":"Kudlay","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, I.M. 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