The research team, led by investigators affiliated with Zhongshan Hospital of Fudan University, began with a spontaneous intestinal tumor model, the Apc-Min mouse, in which animals were placed on a 5:2 intermittent fasting schedule consisting of two nonconsecutive 24-hour fasts per week. Compared with mice fed ad libitum, the fasting animals gained less body weight and, more importantly, carried a markedly reduced intestinal tumor burden, with fewer and smaller tumors and diminished Ki-67 staining indicating slower tumor-cell proliferation. Immunostaining revealed denser infiltration of CD3-positive CD8-positive T cells within the fasting-treated tumors, and flow cytometry showed that these T cells were functionally energized, expressing higher levels of the effector molecules interferon-gamma and granzyme B while displaying reduced PD-1, a marker associated with exhaustion.

To confirm that CD8-positive T cells were not merely bystanders, the researchers depleted them with a specific antibody in a syngeneic MC38 colorectal cancer model. The depletion largely abolished the tumor-suppressive effect of fasting, establishing that the dietary intervention works through, rather than alongside, this cytotoxic lymphocyte population. In the same model, fasting increased levels of the immunogenic stress signals HMGB1 and interferon-beta in tumor interstitial fluid, the extracellular fluid bathing the tumor, along with elevated SEC61-beta expression in tumor tissue, an early hint that a distinctive form of endoplasmic reticulum stress was underway inside the malignant cells.

The search for the responsible metabolite turned to untargeted serum metabolomics in the fasting and freely fed mice. Among the most prominently reduced metabolites was taurine, a finding validated by direct quantification in serum, tumor interstitial fluid, and tumor tissue. Because the liver is a major site of taurine biosynthesis, the team measured hepatic cysteine dioxygenase 1, a rate-limiting enzyme upstream of taurine production, and found that fasting suppressed its expression, pointing to reduced systemic taurine synthesis. The functional test was decisive: oral taurine supplementation largely reversed the tumor suppression achieved by fasting, whereas guanidinoethyl sulfonate, an inhibitor of the taurine transporter SLC6A6, suppressed tumor growth even under unrestricted feeding. In human tissue cohorts, high SLC6A6 expression in colorectal tumors correlated negatively with CD8-positive T-cell abundance and predicted poorer overall survival, while taurine concentrations in tumor interstitial fluid rose progressively from normal mucosa through adenoma to carcinoma.

The mechanistic centerpiece of the study is the identification of GRP78, the endoplasmic reticulum’s master chaperone, as a direct taurine-associated protein. Using a drug affinity responsive target stability screen coupled to mass spectrometry, the researchers found that taurine protected GRP78 from proteolytic digestion in a dose-dependent manner, and a biotinylated taurine pulldown assay confirmed physical enrichment of GRP78 that could be competed away by excess free taurine. The downstream consequence was selective: in tumors from fasting mice, the PERK arm of the unfolded protein response lost protein abundance while IRE1-alpha and ATF6 remained unchanged, and messenger RNA levels of all the relevant genes were untouched, indicating that fasting regulates PERK post-translationally.

Under short-term starvation in cultured cells, PERK protein decayed after protein synthesis was blocked with cycloheximide, but taurine supplementation preserved PERK in a concentration-dependent fashion. Proteasome inhibition with MG132 partially rescued PERK, implicating ubiquitin-dependent degradation, and indeed starvation increased PERK ubiquitination while taurine attenuated it. Starvation also weakened the physical association between GRP78 and PERK, an interaction taurine restored. When the researchers knocked down GRP78, taurine lost much of its ability to stabilize PERK, cementing the chaperone as the mediator through which the metabolite exerts its protective effect on the stress kinase.

What happens when PERK disappears under nutrient stress proved to be the most striking discovery of the study. PERK-deficient colorectal cancer cells exposed to starvation developed extensive cytoplasmic vacuolization and endoplasmic reticulum swelling, hallmarks of paraptosis, a non-apoptotic, caspase-independent form of regulated cell death. A pharmacological screen showed that inhibitors of apoptosis, necroptosis, ferroptosis, pyroptosis, and autophagy failed to rescue the cells, whereas blocking protein synthesis did. Critically, taurine supplementation could not reverse the vacuolization or the death once PERK was gone, demonstrating that the metabolite acts upstream of the kinase rather than on the death program itself. The dying cells also became immunologically loud: they exposed calreticulin on their surface, released HMGB1, produced interferon-beta, and were killed more efficiently by peripheral blood mononuclear cells, which in turn activated type I interferon signaling programs.

In living animals, PERK knockdown in MC38 tumors reproduced the fasting phenotype, suppressing growth, increasing CD8-positive T-cell infiltration and activation, expanding antigen-presenting conventional dendritic cells, shrinking myeloid-derived suppressor cell populations, and shifting macrophages toward an inflammatory M1-like state. A bilateral tumor model revealed that a PERK-deficient tumor could even slow the growth of a genetically intact tumor implanted on the opposite flank, evidence of a systemic immune response. Transcriptomic analysis identified ERO1A, a CHOP-associated endoplasmic reticulum stress gene, as the dominant fasting-suppressed output of the PERK axis; ERO1A overexpression accelerated tumor growth and blunted T-cell activity, while ERO1A restoration in PERK-deficient tumors partially rescued tumor volume and reversed the immune activation, confirming it as a functional downstream effector.

The translational payoff came in combination experiments with immune checkpoint blockade. In both MC38 and CT26 syngeneic models, intermittent fasting plus anti-PD-1 antibody suppressed tumor growth more effectively than either treatment alone, and the transporter inhibitor guanidinoethyl sulfonate similarly strengthened PD-1 blockade in CT26 tumors. The authors propose a coherent model in which fasting restricts systemic and intratumoral taurine, disrupting taurine-dependent GRP78 maintenance of PERK, dismantling the ATF4-CHOP-ERO1A stress-adaptation axis, and converting nutrient stress from a survival buffer into paraptosis-like immunogenic cell death that fuels CD8-positive T-cell immunity. The team acknowledges open questions, including the unresolved structural basis of the taurine-GRP78-PERK interface and the need for paired metabolomic and immune-profiling data from the same human specimens. Still, the work suggests that taurine restriction, whether through dietary scheduling or transporter inhibition, could offer a metabolically grounded strategy to convert immunologically cold colorectal tumors into ones that respond to immunotherapy.

Subject of Research: Taurine restriction and PERK attenuation in intermittent fasting-mediated antitumor immunity in colorectal cancer

Article Title: Intermittent Fasting Reduces Taurine Availability and Promotes Antitumor Immunity Through PERK Attenuation‐Associated Paraptosis‐Like Cell Death in Colorectal Cancer

Article References: Song, B., Kam, S., Liu, J., Lv, R., Huo, X., Chen, Z., Dong, Y., Cai, S., Li, B., Ren, R., Zhong, Y., & Cai, M. (2026). Intermittent Fasting Reduces Taurine Availability and Promotes Antitumor Immunity Through PERK Attenuation‐Associated Paraptosis‐Like Cell Death in Colorectal Cancer. Advanced Science, Article e78107. https://doi.org/10.1002/advs.78107

Image Credits: AI Generated

DOI: 10.1002/advs.78107

Keywords: intermittent fasting, taurine, colorectal cancer, PERK, GRP78, paraptosis, CD8 T cells, SLC6A6, ERO1A, anti-PD-1, tumor immunology, metabolomics