HSP90 inhibition drives GRP78 relocalization to potentiate CAR-based immunotherapy during tumor evolution
Tumor evolution under therapeutic pressure promotes drug resistance through adaptive proteostasis buffering. HSP90 is a key molecular chaperone that stabilizes mutated proteins and supports tumor adaptation. Whether disrupting this stress-buffering system can improve immunotherapy remains unclear. Using evolving tumor models of multikinase inhibitor-resistant (MKIR) hepatocellular carcinoma (HCC) and patient samples, we demonstrate that low-dose HSP90 inhibition precisely induces relocalization of GRP78 from the endoplasmic reticulum to the tumor cell surface via DnaJ heat shock protein family (Hsp40) member C1 (DNAJC1)-dependent trafficking. This stress-induced tumor antigen (SITA) converts GRP78 into a therapeutically targetable surface antigen and enhances susceptibility to GRP78-directed CAR-NK cells. In xenograft and syngeneic tumor models, proteostasis perturbation of the HSP90-GRP78 axis enhances CAR-NK and CAR-T activity and promotes NK cell and macrophage infiltration within GRP78-high tumor niches. Collectively, these findings uncover a previously unrecognized concept of a SITA, whereby adaptive proteostasis buffering in evolving tumors can be rewired to enable precise CAR-directed immunotherapy against solid tumors.
Authors
- Luke Fritzky (ORCID: https://orcid.org/0009-0003-3061-2673)
- Kristy Fu
- William C. Gause (ORCID: https://orcid.org/0000-0002-8062-4790)
- Xuening Wang (ORCID: https://orcid.org/0000-0002-7923-4162)
- Keri E. Lunsford (ORCID: https://orcid.org/0000-0002-4156-1774)
- Aimee M. Beaulieu (ORCID: https://orcid.org/0000-0002-7301-0002)
- Joseph J. Bulatowicz
- Maeve Byrne
- Sopio Simonishvili
- Raymond B. Birge (ORCID: https://orcid.org/0000-0002-0721-4672)
- Sajjan Rajpoot (ORCID: https://orcid.org/0000-0003-4126-7011)
- Ailin Mayorga
- Chen Liu (ORCID: https://orcid.org/0000-0002-7797-3869)
- Chang Liu (ORCID: https://orcid.org/0000-0003-0828-1567)
- Fei Chen (ORCID: https://orcid.org/0000-0003-2308-3649)
- Dongfang Liu (ORCID: https://orcid.org/0000-0002-7295-8088)
- Zhongren Zhou
- María Alejandra Cruz (ORCID: https://orcid.org/0000-0003-0986-6751)
- Youssef Sabha
- Anastasia Xynogala (ORCID: https://orcid.org/0009-0005-7377-5549)
- Zhi Wei (ORCID: https://orcid.org/0000-0001-6059-4267)
- Xuxiang Zhang
- Alexander Lamenze
- Alyna Ai
- Yong Qin
- Chih-hsiung Chen
- John Haggerty
- Jong Hyun Cho
Institutions
- Rutgers, The State University of New Jersey (US)
- New Jersey Institute of Technology (US)
- Robert Wood Johnson University Hospital (US)
- Johnson University (US)
- Yale University (US)
Publication Details
- Journal
- Molecular Cancer
- Published
- 2026-10-03
- DOI
- https://doi.org/10.1186/s12943-026-02807-2
- Primary Topic
- Heat shock proteins research
- Type
- article
- Field-Weighted Citation Impact
- 0.00