Document Type

Article

Publication Date

3-16-2026

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This article is the author's final published version in Frontiers in Immunology, Volume 17, March 2026, Article Number 1772472.

The published version is available at https://doi.org/10.3389/fimmu.2026.1772472. Copyright © 2026 Cao, Alvarez, Mitra, Xu, Baybutt, Sun, Taylor, Doermann, Staudt, Waldman and Snook.

Abstract

INTRODUCTION: FDA-approved chimeric antigen receptor (CAR)-expressing T cell therapies (CARTs) have revolutionized the treatment of blood cancers. Yet none have been successful for "solid" tumors, such as colorectal cancer (CRC), the 2nd leading cause of cancer deaths. Guanylyl cyclase C (GUCY2C) has emerged as a clinical-stage target for CART and bispecific T-cell engager (BiTE) therapies in CRC. IFNγ has been canonically recognized as beneficial for the effector functions of T cells by enhancing antigen processing and HLA presentation and is essential for CART targeting of solid malignancies by inducing adhesion molecule expression for synapse stabilization.

METHODS: Using

RESULTS: We identified a novel antigen loss mechanism that limits the efficacy of CART in CRC, in which IFNγ secreted by activated CART cells causes bystander cancer cells to lose GUCY2C. This previously unexplored antigen loss mechanism is mediated through IFNγ receptor, JAK, and cellular stress signaling pathways. This mechanism of antigen loss can be rescued with anti-IFNγ neutralizing antibody, the JAK inhibitor ruxolitinib, or 4-phenylbutyrate (an ER stress reliever).

DISCUSSION: We revealed a negative effect of IFNγ that uniquely interferes with immunotherapies targeting native surface antigens, such as CART and BiTE therapies, which may be reversed by disrupting stress signaling pathways to enhance solid tumor CART and BiTE immunotherapies.

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Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Language

English

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