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Macrophages, with their natural ability to infiltrate tumors, modulate immunity, and phagocytose cancer cells, offer a promising alternative when engineered with CARs. While studies have demonstrated the feasibility and anti-tumor activity of CAR macrophages (CAR-M), enhancing their persistence and phagocytic capacity remains a key challenge.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>\n                      Building on first-generation CD3\u03b6-based CAR-M, we developed a novel CAR targeting human GPC3, incorporating IFN-\u03b3 and the extracellular domain of SIRP\u03b1 (SIRP\u03b1\n                      <jats:sup>ECD<\/jats:sup>\n                      ) to improve CAR-M persistence and block the CD47\u2013SIRP\u03b1 immune checkpoint. Following delivery via lipid nanoparticle-encapsulated mRNA (LNP-mRNA), the self-secreted IFN-\u03b3 sustained M1 polarization through phospho-STAT1 activation. Meanwhile, the ectopically expressed SIRP\u03b1\n                      <jats:sup>ECD<\/jats:sup>\n                      competitively bound to CD47 on tumor cells, thereby blocking the endogenous SIRP\u03b1\u2013SHP2 interaction in a dominant-negative manner. This design enhanced pro-inflammatory activity and anti-tumor efficacy compared to CD3\u03b6-only CAR-M. Single-cell RNA sequencing and cellular analysis showed that in situ programmed CAR-M reprogrammed the tumor microenvironment toward inflammation in a murine hepatocellular carcinoma (HCC) model. Moreover, CAR-M derived from human peripheral blood mononuclear cells (PBMCs) effectively phagocytosed human HCC organoids while sparing healthy tissues, indicating clinical potential.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Collectively, our work presents a novel CAR design that enhances phagocytic function and sustains anti-tumor activity, offering a promising strategy for human solid tumor immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12951-026-04593-x","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T08:47:16Z","timestamp":1779785236000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["An in situ generated CAR-M with IFN-\u03b3 and negative dominance Sirp\u03b1 isoform augments hepatocellular carcinoma immunotherapy"],"prefix":"10.1186","volume":"24","author":[{"given":"Xiang","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongceng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanrong","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonglong","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panpan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"issue":"6","key":"4593_CR1","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1038\/s41571-019-0184-6","volume":"16","author":"NN Shah","year":"2019","unstructured":"Shah NN, Fry TJ. 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