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U.S.A."],"published-print":{"date-parts":[[2025,10,14]]},"abstract":"<jats:p>Tumor-targeted T cell therapies of various types have been booming, but T cell therapy is limited by its inability to penetrate the collagen barrier surrounding tumors. The destruction of tumor collagen is significant because collagen both suppresses T cells and contributes to the formation of the extracellular matrix. Our previously reported cell-surface vimentin (CSV)\u2013targeted and membrane-anchored interleukin 12-armed (attIL12) T cells can reduce collagen production by killing cancer-associated fibroblasts, but fail to reduce collagen expression by tumor cells, resulting in resistance to attIL12-T cell treatment. In this study, we found that CCKAR directly boosts collagen production by tumor cells in vitro and in vivo. attIL12-modified tumor-infiltrating lymphocytes (TILs) disabled collagen production by CCKAR-high autologous tumor cells in vitro and sarcoma patient-derived xenografts (PDXs) in vivo. This disruption of collagen production by tumor cells by attIL12-TILs overcomes resistance to attIL12-T cell treatment and required a simultaneous interaction between the CSV on autologous tumor cells, which is targeted by attIL12, and human leukocyte antigen-T cell receptor on attIL12-TILs; When either interaction was abrogated, collagen production and CCKAR expression were not shut down. Mechanistically, the interaction between attIL12-TILs and autologous tumor cells induced interferon gamma production synergistically, which in combination with CCKAR downregulation reduced collagen expression through suppression of both transforminggrowth factor beta-stimulated SMAD activation and CCKAR-AKT signaling. Diminishing collagen expression from tumor cells significantly increased T cell infiltration and improved tumor growth inhibition in PDX sarcomas. Thus, this attIL12-TIL therapy holds great clinical potential for boosting T cell infiltration in high-grade, collagen-rich tumors.<\/jats:p>","DOI":"10.1073\/pnas.2507542122","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T19:04:23Z","timestamp":1759777463000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Collagen-disrupting attIL12 TIL therapy boosts deep T cell infiltration via dual signaling activation and CCKAR reduction in sarcomas"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5142-0641","authenticated-orcid":false,"given":"Jiemiao","family":"Hu","sequence":"first","affiliation":[{"name":"Division of Pediatrics, Department of Pediatrics\u2013Research, The University of Texas MD Anderson Cancer Center","place":["Houston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6314-5790","authenticated-orcid":false,"given":"Harjeet","family":"Singh","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Department of Pediatrics\u2013Research, The University of Texas MD Anderson Cancer Center","place":["Houston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yining","family":"Jin","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Department of Pediatrics\u2013Research, The University of Texas MD Anderson Cancer Center","place":["Houston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7117-1574","authenticated-orcid":false,"given":"Wendong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Department of Pediatrics\u2013Research, The University of Texas MD Anderson Cancer Center","place":["Houston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, The University of Texas MD Anderson Cancer Center","place":["Houston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqing","family":"Xia","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Department of Pediatrics\u2013Research, The University of Texas MD Anderson Cancer Center","place":["Houston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0146-7732","authenticated-orcid":false,"given":"Neeta","family":"Somaiah","sequence":"additional","affiliation":[{"name":"Division of Cancer Medicine, Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center","place":["Houston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8995-2929","authenticated-orcid":false,"given":"Richard","family":"Gorlick","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Department of Pediatrics\u2013Research, The University of Texas MD Anderson Cancer Center","place":["Houston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5657-4183","authenticated-orcid":false,"given":"Shulin","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Department of Pediatrics\u2013Research, The University of Texas MD Anderson Cancer Center","place":["Houston"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2023.102668"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30006-8"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30624-1"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.32.2537"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.58.0225"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0391-1"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-007697"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0000000000000355"},{"key":"e_1_3_4_9_2","first-page":"A190","article-title":"Expansion of tumor-infiltrating lymphocytes and marrow-infiltrating lymphocytes from pediatric malignant solid tumors","volume":"9","author":"Metts J.","year":"2021","unstructured":"J. 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