SPTBN2 promotes an immunosuppressive tumor microenvironment and cross-resistance to anti-cancer therapies
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' 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.
Authors
- Crystal S. Conn (ORCID: https://orcid.org/0000-0003-3209-0445)
- Erik Nash
- Ágnes Holczbauer (ORCID: https://orcid.org/0000-0002-1786-9146)
- Serge Y. Fuchs (ORCID: https://orcid.org/0000-0002-0136-5103)
- Wei Guo (ORCID: https://orcid.org/0000-0002-9251-0360)
- Mayura Dhamdhere (ORCID: https://orcid.org/0000-0002-6062-7943)
- Luca Paruzzo (ORCID: https://orcid.org/0000-0002-6505-0194)
- Puneeth Guruprasad (ORCID: https://orcid.org/0000-0001-9615-1935)
- Ben Z. Stanger (ORCID: https://orcid.org/0000-0003-0410-4037)
- Vladimir S. Spiegelman (ORCID: https://orcid.org/0000-0003-4847-155X)
- Hallgeir Rui (ORCID: https://orcid.org/0000-0002-8778-261X)
- Quoc Thang Bui
- Matthew J. Atherton (ORCID: https://orcid.org/0000-0002-9830-3151)
- Will Bailis (ORCID: https://orcid.org/0000-0001-9420-6250)
- Michael Scaglione (ORCID: https://orcid.org/0000-0003-2953-1748)
- Raghavendra Basavaraja (ORCID: https://orcid.org/0000-0002-8656-2615)
- Constantinos Koumenis (ORCID: https://orcid.org/0000-0001-5945-4726)
- Marco Ruella (ORCID: https://orcid.org/0000-0003-4301-5811)
- Daniel P. Beiting (ORCID: https://orcid.org/0000-0002-2865-4589)
- Yu Sun (ORCID: https://orcid.org/0000-0003-2392-2043)
- J. Alan Diehl
- Yi Fan
- Lynn Spruce
- Kai Tan
- Yingying Tang
- Alice Wang
Institutions
- Children's Hospital of Philadelphia (US)
- Thomas Jefferson University (US)
- Case Western Reserve University (US)
- University of Pennsylvania (US)
- Penn State Milton S. Hershey Medical Center (US)
- Philadelphia University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-04-01
- DOI
- https://doi.org/10.64898/2026.03.30.715365
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00