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

Senescent cells are cells that have permanently stopped dividing, often in response to DNA damage or stress. Rather than simply retiring quietly, they remain metabolically active and secrete a cocktail of proinflammatory molecules known as the senescence-associated secretory phenotype, or SASP. While this process plays a role in wound healing and tumor suppression in the short term, the gradual accumulation of senescent cells in tissues drives chronic inflammation and has been implicated in conditions ranging from frailty and diabetes to liver fibrosis and cancer. Eliminating these cells, an approach called senolysis, has therefore become one of the most actively pursued strategies in geroscience.

The problem, according to the research team led by Jianghao Qian and Akiko Takahashi, is that most current senolytic drugs work by targeting antiapoptotic pathways that senescent cells deploy to avoid self-destruction. These drugs, including the best-known combination of dasatinib and quercetin, can be effective but carry dose-dependent toxicity that limits their clinical utility. The Japanese team set out to find a fundamentally different way to kill senescent cells, and their search led them to an unexpected candidate: a forty-year-old immunosuppressant sitting in hospital pharmacies around the world.

Their findings reveal that cyclosporine A kills senescent cells through paraptosis-like cell death, a caspase-independent process that does not rely on the conventional apoptosis machinery targeted by existing senolytics. In paraptosis, cells die through dramatic swelling and vacuolization of the endoplasmic reticulum and mitochondria rather than through the orderly fragmentation characteristic of apoptosis. Using live-cell holotomography imaging, the researchers directly visualized this distinctive death process unfolding in senescent cells treated with the drug.

The mechanism behind this selectivity is elegant in its exploitation of a senescent cell’s own weakness. The team discovered that cyclosporine A activates JNK signaling and elevates production of reactive oxygen species, which in turn triggers the apoptosis signal-regulating kinase 1, or ASK1, and its downstream partner, the p38 mitogen-activated protein kinase pathway. Rather than suppressing inflammation as it does in immune cells, the drug amplifies SASP factor expression in senescent cells, dramatically increasing their secretory output.

This SASP overactivation turns out to be lethal precisely because senescent cells are already operating at the limit of their protein-handling capacity. The researchers showed that senescent cells inherently exhibit chronic adaptive endoplasmic reticulum stress responses and heightened ER functional demands, a direct consequence of their extensive secretory activity. The endoplasmic reticulum is the cellular organelle responsible for folding and processing the vast majority of secreted proteins, and the constant flood of inflammatory SASP factors places an enormous burden on this system. When cyclosporine A further disrupts this fragile ER homeostasis by forcing SASP overexpression, the organelle swells catastrophically, and the cell succumbs to paraptosis-like death.

In other words, the very trait that makes senescent cells harmful to tissue, their relentless secretion of inflammatory mediators, becomes the vulnerability that cyclosporine A exploits. Healthy nonsenescent cells, which do not carry this chronic ER stress burden, tolerate the drug at concentrations that prove lethal to their senescent counterparts, providing a mechanistic basis for the drug’s selectivity.

The therapeutic implications were tested directly in an animal model of obesity-associated liver cancer. Obese mice accumulate senescent hepatic stellate cells in their livers, and these cells promote the development of hepatocellular carcinoma by sustaining the inflammatory microenvironment that feeds tumor growth. When the researchers treated obese mice with cyclosporine A, the drug eliminated the senescent stellate cells from the liver and, remarkably, prevented the development of obesity-associated hepatocellular carcinoma. This finding suggests that senolysis via paraptosis could be deployed not merely to slow aging but to intervene in specific cancers driven by senescent cells in the tumor microenvironment.

The study represents a significant conceptual expansion of the senolytic toolkit. By demonstrating that ER stress-induced paraptosis-like cell death can serve as a viable senolysis strategy, the work establishes an entirely new mechanistic class of senotherapy, one that targets the proteostatic fragility of senescent cells rather than their apoptotic defenses. Because cyclosporine A is already an approved clinical drug with well-characterized pharmacology, the path from bench to bedside could be considerably shorter than for entirely novel compounds, although the researchers caution that dose, duration, and the drug’s immunosuppressive effects will all need careful evaluation in the context of senotherapy.

More broadly, the findings add to a growing recognition that aging cells can be eliminated by exploiting metabolic and stress-response vulnerabilities unique to their state. If ER stress amplification proves safe and effective in humans, the strategy could eventually be applied across a broad spectrum of age-related disorders, from fibrotic liver disease to inflammation-driven tumors, offering a way to turn a decades-old transplant drug into a weapon against the biology of aging itself.

Subject of Research: Senolysis via cyclosporine A-induced endoplasmic reticulum stress and paraptosis-like cell death in senescent cells

Article Title: Cyclosporine A provokes paraptosis-like cell death in senescent cells by triggering endoplasmic reticulum stress

Article References: Qian, J., Zhou, X., Lee, K.-S., Loo, T. M., Tanaka, Y., Sugawara, S., Hanyu, A., Kawasaki, H., Yotsumoto, S., Dodo, K., Shirasaki, Y., Kamatani, T., Tanaka, K., & Takahashi, A. (2026). Cyclosporine A provokes paraptosis-like cell death in senescent cells by triggering endoplasmic reticulum stress. Genome Biology. https://doi.org/10.1186/s13059-026-04273-x

Image Credits: AI Generated

DOI: 10.1186/s13059-026-04273-x

Keywords: cellular senescence, senolysis, cyclosporine A, endoplasmic reticulum stress, paraptosis, SASP, hepatocellular carcinoma, aging, cell death, senolytics, Cyclosporine, provokes