{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T21:26:00Z","timestamp":1775251560320,"version":"3.50.1"},"posted":{"date-parts":[[2026,4,1]]},"group-title":"Cancer Biology","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Cancer Institute","award":["R01 CA285321"],"award-info":[{"award-number":["R01 CA285321"]}]},{"name":"National Cancer Institute","award":["R01 CA288849"],"award-info":[{"award-number":["R01 CA288849"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Immunosuppressive tumor microenvironment (TME) inactivates CD8+ cytotoxic lymphocytes (CTLs). Here, we identify SPTBN2 spectrin as a key immunosuppressive regulator induced in CTLs in response to nutritional deficit. In human pancreatic and colorectal cancers, SPTBN2 expression negatively correlated with CTL infiltration and patients\u2019 survival. In TME of mouse pancreatic and colorectal adenocarcinomas, SPTBN2 inactivated intratumoral CTLs, stimulated tumor growth and conferred cross-resistance to anti-cancer therapies. SPTBN2 knockout protected CAR T-cells from trogocytosis and increased their memory state. SPTBN2 maintained levels of cell surface proteins such as BTLA that undermine CAR T-cell cytotoxicity and promote exhaustion. Re-expression of BTLA largely reversed phenotypes in SPTBN2-deficient CAR T-cells. In manufactured CAR T cells, SPTBN2 was associated with their clinical failure in pediatric patients with leukemia. Accordingly, ablation of SPTBN2 in CAR T-cells increased their cytotoxicity, in vivo persistence and therapeutic effects indicating that SPTBN2 can be targeted to increase the efficacy of anti-cancer therapies.<\/jats:p>","DOI":"10.64898\/2026.03.30.715365","type":"posted-content","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T02:51:05Z","timestamp":1775098265000},"source":"Crossref","is-referenced-by-count":0,"title":["SPTBN2 promotes an immunosuppressive tumor microenvironment and cross-resistance to anti-cancer therapies"],"prefix":"10.64898","author":[{"given":"Quoc Thang","family":"Bui","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raghavendra","family":"Basavaraja","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mayura R.","family":"Dhamdhere","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c5gnes","family":"Holczbauer","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Paruzzo","sequence":"additional","affiliation":[{"name":"Dept. of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Puneeth","family":"Guruprasad","sequence":"additional","affiliation":[{"name":"Dept. of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Scaglione","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingying","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuchen","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel P.","family":"Beiting","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik K.","family":"Nash","sequence":"additional","affiliation":[{"name":"Proteomics Core Facility, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hossein","family":"Fazelinia","sequence":"additional","affiliation":[{"name":"Proteomics Core Facility, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynn A.","family":"Spruce","sequence":"additional","affiliation":[{"name":"Proteomics Core Facility, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alice","family":"Wang","sequence":"additional","affiliation":[{"name":"Graduate Group in Genomics and Computational Biology, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Guo","sequence":"additional","affiliation":[{"name":"Dept. of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Crystal S.","family":"Conn","sequence":"additional","affiliation":[{"name":"Dept. of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Fan","sequence":"additional","affiliation":[{"name":"Dept. of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, 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