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Alliance"],"accepted":{"date-parts":[[2024,8,19]]},"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:p>\n                    HER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor-associated macrophages (TAMs). Although TAMs consist of the immune-stimulatory M1 type and immune-suppressive M2 type, the M1\/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1- versus M2-TAM formation depends on differential arginine metabolism, where M1-TAMs convert arginine to nitric oxide (NO) and M2-TAMs convert arginine to polyamines (PAs). We hypothesize that such distinct arginine metabolism in M1- versus M2-TAMs is attributed to different availability of BH\n                    <jats:sub>4<\/jats:sub>\n                    (NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH\n                    <jats:sub>4<\/jats:sub>\n                    precursor, elevates the expression of M1-TAM markers within HER2+ tumors. Here, we show that SEP restores BH\n                    <jats:sub>4<\/jats:sub>\n                    levels in M2-like macrophages, which then redirects arginine metabolism to NO synthesis and converts M2 type to M1 type. The reprogrammed macrophages exhibit full-fledged capabilities of antigen presentation and induction of effector T cells to trigger immunogenic cell death of HER2+ cancer cells. This study substantiates the utility of SEP in the metabolic shift of the HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.\n                  <\/jats:p>","DOI":"10.26508\/lsa.202302339","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T15:35:14Z","timestamp":1724772914000},"page":"e202302339","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Reprogramming of breast tumor\u2013associated macrophages with modulation of arginine metabolism"],"prefix":"10.26508","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4759-653X","authenticated-orcid":true,"given":"Veani","family":"Fernando","sequence":"first","affiliation":[{"name":"Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, Toledo, OH, USA"},{"name":"Division of Rheumatology, University of Colorado, Anschutz Medical 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