Trending Topics in Gastroenterology | GastroAGI

Quality of Life vs Survival in Older Adults With Advanced Cancer Source: JAMA Oncology, March 2026

Introduction Treatment decisions in advanced cancer often involve a balance between extending survival and preserving quality of life (QoL). Older adults frequently face complex choices because aggressive treatments may prolong life but also increase toxicity, hospitalisations, and functional decline. Understanding whether patient preferences influence real-world outcomes is essential for patient-centred oncology care. Summary This secondary analysis evaluated 706 adults aged ≥70 years with advanced incurable cancers enrolled in the GAP70+ trial. Patients were categorised based on whether they prioritised maintaining quality of life or prolonging survival when starting systemic therapy. 71.7% (506 patients) prioritised quality of life 8.4% (59 patients) prioritised survival The most common cancers were gastrointestinal (34.6%), lung (24.8%), and genitourinary (15.4%) Despite differing priorities, clinical outcomes were similar between groups: No difference in treatment modifications No difference in grade 3–5 treatment-related adverse effects No difference in hospitalisation rates No difference in survival at 6 months or 1 year Key Message Most older adults with advanced cancer prefer maintaining quality of life over extending survival, yet this preference did not translate into different treatment approaches or outcomes, suggesting that current oncology care systems may not adequately align treatment decisions with patient preferences.

Rethinking TNT in Rectal Cancer: J Clin Oncol March 26

Introduction Total neoadjuvant therapy (TNT) has become a major advance in locally advanced rectal cancer, helping improve systemic control, increase tumor response, and expand the possibility of organ preservation. However, most trials and guidelines still treat rectal cancer as a single disease entity. This review argues that this is an oversimplification. Tumor location matters, especially when comparing mid-rectal and low-rectal cancers, because anatomy, lymphatic drainage, surgical difficulty, functional impact, and treatment goals differ substantially. Summary This review highlights that low-rectal cancers and mid-rectal cancers should be approached as distinct clinical entities rather than managed uniformly. Low-rectal tumors, particularly those within 1 cm of the anal ring, present special challenges. They have more complex local anatomy, more difficult lymphatic patterns, a higher risk of positive circumferential margins, and major implications for continence, sphincter preservation, and quality of life. In these tumors, a more intensive TNT strategy may be justified, especially when the goal is organ or sphincter preservation. In contrast, mid-rectal tumors are often more straightforward surgically, with a better chance of standard resection and preservation of function. For these cancers, the review suggests that treatment de-escalation, particularly regarding radiotherapy, may be reasonable in selected patients. Drawing on data from more than 80 studies and trials, the authors propose a location-specific, patient-centred strategy: De-escalate treatment in selected mid-rectal cancers Intensify or optimise TNT in low-rectal cancers when preservation is a priority Take-home message The key disruptive idea is simple: rectal cancer is not one disease anatomically or functionally. Future TNT strategies should be tailored by tumor height, oncologic risk, and patient priorities, not applied uniformly.

Obesity and Cancer: JAMA March 2026

Why this review matters Obesity is no longer viewed only as a metabolic disorder; it is now a major cancer-promoting state. This review explains how excess adiposity drives cancer through intertwined biologic pathways, including chronic inflammation, hormonal dysregulation, immune suppression, altered energy metabolism, DNA damage, and gut microbiome disruption. For clinicians, the key message is practical: obesity is a modifiable cancer risk factor, and meaningful weight loss may reduce future cancer burden. Main clinical message Overweight and obesity are associated with higher rates of multiple cancers, especially endometrial, colorectal, liver, gallbladder, pancreas, kidney, postmenopausal breast, oesophagal adenocarcinoma, ovarian, thyroid, gastric, prostate, and multiple myeloma. The review estimates that obesity contributes to about 10% of new cancers annually in the US, and even more in selected tumour types such as endometrial and hepatobiliary malignancies. Key biologic pathways The review highlights 5 major mechanisms: 1. Adipose tissue dysfunction: enlarged adipocytes produce excess estrogens, leptin, inflammatory cytokines, and less adiponectin. 2. Chronic inflammation: IL-6, TNF-α, prostaglandin E2, and related mediators create a pro-tumor microenvironment. 3. Immune escape: obesity impairs cytotoxic T cells and NK cells while increasing immunosuppressive myeloid-derived suppressor cells. 4. Metabolic support for tumours: adipose tissue supplies free fatty acids and other fuels for cancer growth. 5. DNA damage and microbiome changes: oxidative stress and dysbiosis increase genomic instability and mucosal inflammation. Important epidemiologic insights Cancer risk is not determined by BMI alone. Patients with metabolically unhealthy obesity appear to have the highest cancer risk. The review also stresses that childhood and adolescent obesity trajectories may influence cancer risk later in life. Interestingly, obesity increases postmenopausal breast cancer risk, but may show a different association before menopause. Weight loss and cancer prevention The review suggests that modest weight loss may not be enough. A threshold of more than 10% body weight reduction may be needed to produce measurable reductions in obesity-related cancer risk. Observational data suggest benefit with: Bariatric surgery, especially for endometrial cancer risk reduction GLP-1 receptor agonists, with retrospective data suggesting a lower incidence of some obesity-related cancers Metformin and related metabolic therapies, though stronger prospective evidence is still needed Practice implications Clinicians should view obesity management as part of long-term cancer prevention, not only cardiovascular and metabolic risk reduction. Counselling should move beyond BMI to include metabolic health, waist circumference, adiposity pattern, and sustained weight-loss strategies. Multimodal care combining lifestyle measures, pharmacotherapy, and, in selected patients, bariatric surgery may have future oncologic relevance. Limitations of the review Much of the evidence linking weight loss interventions to lower cancer incidence remains observational, not randomised. Several mechanistic pathways are strongly biologically plausible but not yet fully translated into cancer prevention trials. Bottom line Obesity promotes cancer through multiple biologic pathways, and meaningful sustained weight loss may reduce this risk. This review strengthens the concept that treating obesity is also part of cancer prevention.

FIT vs Colonoscopy: COLONPREV Trial- Gastroenterology | March 2026

Introduction Colorectal cancer (CRC) screening strategies vary worldwide, with fecal immunochemical testing (FIT) widely used in population programs and colonoscopy dominating screening in the United States. The COLONPREV randomized trial previously showed that FIT-based screening was not inferior to colonoscopy for CRC incidence and mortality at 10 years, despite higher participation rates with FIT. However, colonoscopy consistently detects more premalignant lesions. This analysis explored an important clinical question: are the characteristics of precursor lesions different when detected through FIT-triggered colonoscopy versus primary screening colonoscopy? Summary This analysis from the COLONPREV trial compared colonoscopic findings in individuals undergoing primary screening colonoscopy with those undergoing colonoscopy after a positive FIT result. While colonoscopy detected more overall precursor lesions, individuals referred after abnormal FIT were significantly more likely to harbor advanced neoplastic lesions, including larger polyps (mean size 7.8 mm vs 5.6 mm), higher rates of villous architecture, and high-grade dysplasia. FIT-detected lesions were also more difficult to manage endoscopically, with higher rates of incomplete resection and surgical treatment. Despite these differences, lesion histology and anatomical distribution were similar between strategies. These findings suggest that FIT acts as a risk-stratification tool, enriching for clinically significant lesions among those referred for colonoscopy. Conversely, screening colonoscopy may detect and remove lesions at earlier stages, raising ongoing debate about potential overdiagnosis versus true cancer prevention. Long-term follow-up will determine whether these differences influence CRC incidence and outcomes.

Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline Update: J Clin Oncol | Feb. 2026 | DOI: 10.1200/JCO-25-02958

Introduction Advanced gastroesophageal cancers (gastric, GEJ, oesophagal adenocarcinoma, and ESCC) have entered a biomarker-led era. This ASCO update reframes first-line choices around four core actionable domains—PD-L1, HER2, dMMR/MSI-H, and CLDN18.2—and then clarifies second/third-line options when disease progresses. The practical message is simple: get key biomarkers early, start chemotherapy without delay if needed, and layer immunotherapy/targeted therapy only where the signal is strongest. 20 Key Takeaways for Clinicians (ASCO 2026) Test early, treat smart: For gastroesophageal adenocarcinoma, ASCO recommends upfront testing for HER2, PD-L1, dMMR/MSI-H, and CLDN18.2; for ESCC, test PD-L1 and dMMR/MSI-H. Consider broad NGS where feasible. Do not delay chemotherapy while waiting for biomarker results if the patient is symptomatic or unwell—start the backbone and add targeted/IO once results return. PD-L1 matters, and “higher is better”: The likelihood of benefit from adding immunotherapy increases with higher PD-L1 expression (largest signal at higher cutoffs such as CPS ≥10 in trials). DPYD testing before fluoropyrimidines: ASCO includes a safety note—screen for DPYD variants before 5-FU/capecitabine; avoid fluoropyrimidines in complete DPD deficiency and individualise dose in partial deficiency. pMMR/MSS, HER2-negative adenocarcinoma + PD-L1 ≥1 (and CLDN18.2 negative): Doublet chemo + immunotherapy is recommended as a reasonable first-line option. pMMR/MSS, HER2-negative + PD-L1 <1 + CLDN18.2 positive: Chemo + zolbetuximab should be offered. Dual-positive PD-L1 ≥1 and CLDN18.2 positive (HER2-negative): Either chemo + immunotherapy or chemo + zolbetuximab may be used—shared decision-making is explicitly advised. pMMR/MSS, HER2-negative + PD-L1 <1 + CLDN18.2 negative: Chemo alone remains the standard default. HER2-positive gastric/GEJ adenocarcinoma (pMMR/MSS): Trastuzumab + doublet chemo is standard; if PD-L1 ≥1, add pembrolizumab. dMMR/MSI-H disease (any histology in scope): Immunotherapy is central—ASCO supports immunotherapy with chemo and also allows immunotherapy alone in selected patients (case-by-case). ESCC (unresectable/advanced): If PD-L1 ≥1, offer immunotherapy + chemo; nivolumab + ipilimumab is another option in appropriate patients. ESCC with PD-L1 <1: Chemo alone is acceptable; immunotherapy benefit is less certain at very low PD-L1. Second-line adenocarcinoma backbone: Ramucirumab + paclitaxel remains a key recommended option after progression on first-line therapy. Second-line alternative when taxanes are problematic: Ramucirumab + FOLFIRI can be considered for patients previously exposed to docetaxel or those with troublesome neurotoxicity. Second-line for HER2-positive after progression: Trastuzumab deruxtecan (T-DXd) should be offered. Re-test HER2 after progression on HER2-directed first-line therapy—HER2 can be lost, and treatment should match current biology. Later-line ESCC immunotherapy: If a patient did not receive immunotherapy upfront and has PD-L1 ≥1, nivolumab or tislelizumab may be used; pembrolizumab is a stronger consideration at higher PD-L1 thresholds (e.g., ≥10 in the evidence base). Zolbetuximab toxicity is predictable and manageable: expect nausea/vomiting early, use proactive antiemetics, adjust infusion strategies, and maintain hydration—don’t abandon an effective drug prematurely. Actionable biomarkers are not mutually exclusive: A meaningful minority will have >1 target (e.g., PD-L1 + CLDN18.2). The guideline emphasises patient-centred choice based on PD-L1 level, symptom burden, toxicity profiles, comorbidities, and patient preference. If no actionable biomarker or patient is not a candidate for IO/targeted therapy, fluoropyrimidine + platinum doublet chemotherapy remains the universal fallback—still the most practical global standard.

ICIs in Locally Advanced Rectal Cancer- Gut | Feb. 2026

Introduction Locally advanced rectal cancer (LARC; stage II–III) has traditionally been treated with neoadjuvant chemoradiotherapy (CRT) and total mesorectal excision (TME). While effective for local control, this pathway often delivers modest complete response rates and exposes many patients to long-term bowel, urinary, and sexual dysfunction—especially those with low rectal tumors where a stoma risk and quality-of-life trade-offs are substantial. In parallel, immune checkpoint inhibitors (ICIs) have rapidly shifted the landscape for the dMMR/MSI-H subtype—where deep responses can enable organ preservation in selected patients—while combination strategies (ICI + CRT/TNT) are being explored for pMMR/MSS disease. This Chinese Society of Colorectal Surgery (CNSCRS) consensus provides practical standards for who to treat, how to treat, how to assess response, and how to follow patients, with a strong emphasis on perioperative safety and organ-sparing pathways. Why was this guidance required? Evidence in LARC has expanded quickly over the last ~5 years, with multiple phase 2 programs and evolving real-world practice—particularly around non-operative management after complete response. The “new bottleneck” is no longer whether ICIs work in dMMR/MSI-H disease, but how to operationalise testing, MDT decision-making, response assessment (including pseudoprogression), and safe perioperative management. For pMMR/MSS LARC, enthusiasm for adding ICIs to CRT/TNT is growing, but benefit is heterogeneous, and toxicity attribution is complex—needing standardisation. Key takeaways (Guidance distilled for clinicians) A. Diagnostics and decision-making (Foundational steps) Test MMR/MSI in all LARC before treatment—this is the gateway decision for immunotherapy strategy and Lynch screening. Preferred testing approach: IHC for MMR proteins + PCR for MSI (with validated panels); use certified labs where possible. Do not assume dMMR ≡ MSI-H in every case—discordance exists; dual testing can prevent missed eligibility. Manage LARC with ICIs through a formal MDT (surgery, medical oncology, radiation, radiology, pathology ± gastroenterology/pharmacy) and adjust strategy dynamically as response evolves. B. dMMR/MSI-H LARC (where immunotherapy is most established) Neoadjuvant ICI is a core strategy for stage II–III dMMR/MSI-H LARC; response depth can be substantial and may enable organ preservation in selected patients. Practical rhythm endorsed: treat → assess at ~3 months; if not at a complete clinical response, consider continuing ICIs and reassessing rather than rushing to surgery (with vigilance for non-responders). Organ preservation (watch-and-wait) becomes a realistic goal for motivated mid/low rectal dMMR/MSI-H patients who achieve a robust clinical complete response after adequate ICI exposure. This guidance places strong weight on structured surveillance during watch-and-wait to detect regrowth early (because salvage surgery must remain feasible). If the response is incomplete at ~6 months in a patient seeking organ preservation, the document supports CRT as a “rescue/bridge” strategy in selected high-risk settings, with watch-and-wait still possible if a complete response is achieved after CRT. Pseudoresidual disease/pseudoprogression is real after ICIs: imaging may overcall residual tumour; decisions should integrate endoscopy, MRI, biopsy, and MDT judgment. Adjuvant therapy after neoadjuvant ICI is not standardised; if a patient achieves pathological complete response, observation is reasonable; if residual disease persists, options include continuing the same regimen or switching to standard adjuvant chemotherapy—best individualised. C. pMMR/MSS (or unknown status) LARC (where combinations are exploratory) ICI monotherapy is not a reliable strategy for pMMR/MSS LARC; the guidance focuses on combinations (ICI + CRT/TNT/SCRT) rather than ICI alone. For pMMR/MSS LARC, the consensus supports considering LCRT + 3–6 cycles of ICI (concurrent or sequential) before TME in selected settings, recognising evidence is still largely phase 2 and heterogeneous. For higher-risk disease or technically challenging rectal preservation, TNT + ICI is a reasonable consideration (ideally in trials), with careful monitoring for cumulative toxicity. SCRT-based pathways (SCRT → chemo + ICI) are presented as another acceptable neoadjuvant option, with a practical cap that total immunotherapy duration generally should not exceed ~6 months in these perioperative constructs. Organ preservation in pMMR/MSS should be approached more cautiously than in dMMR/MSI-H; if a true clinical complete response occurs, watch-and-wait can be considered, but patients must be counselled that cCR is less predictable. Dual checkpoint blockade (PD-1 + CTLA-4) is not recommended routinely for pMMR/MSS neoadjuvant/organ-sparing therapy outside trials due to limited efficacy evidence and toxicity concerns. D. Local excision and organ preservation pathways After neoadjuvant ICI-based therapy, local excision can be an organ-sparing option in carefully selected downstaged cases (typically small residual disease), but must be MDT-led with clear salvage plans and high-quality pathology. E. Safety and perioperative management (non-negotiable) Implement baseline screening + active monitoring for immune-related AEs; the guidance flags myocarditis and pneumonitis as rare but high-risk entities requiring early detection systems. Surgery is generally advised after irAEs have recovered to ≤ grade 1, with enhanced perioperative vigilance; an MDT model for irAE management improves diagnostic speed and consistency. Practice-changing or confirmatory? Practice-changing for dMMR/MSI-H LARC (selected patients): This consensus operationalises a real shift: biomarker-first rectal cancer, where dMMR/MSI-H disease can be routed toward ICI-driven organ preservation pathways in experienced centres. The direction of travel is consistent with transformative response signals seen with PD-1 blockade in dMMR rectal cancer. More confirmatory / still-evolving for pMMR/MSS LARC: For MSS disease, this guidance is best read as a structured framework for carefully selected use (preferably trial-enriched) rather than a universal new standard, because long-term survival data and regimen-to-regimen comparisons remain unsettled. Compared with landmark trials MSK dostarlimab (dMMR LARC): The landmark signal that dMMR rectal tumours can achieve profound responses with PD-1 blockade underpins the organ-preservation ambition reflected in this consensus. OPRA (TNT → selective watch-and-wait): OPRA established a modern framework for response-adapted non-operative management after neoadjuvant therapy, showing that structured surveillance and salvage can be oncologically acceptable in well-managed systems—this consensus essentially extends that philosophy into the immunotherapy era (especially for dMMR). NRG-GI002 / pembrolizumab + TNT (mostly MSS): This program highlights the mixed and evolving nature of adding immunotherapy in unselected LARC—supporting the consensus’ cautious tone for pMMR/MSS strategies and its emphasis on trials and careful toxicity attribution. Controversies & unanswered questions What is the “minimum effective duration” of neoadjuvant PD-1 therapy for durable organ preservation in dMMR LARC? (6 months is common, but precision remains uncertain.) How should we define and validate cCR after ICIs? Imaging and endoscopic findings can be misleading due to immune infiltration/fibrosis; standardised response criteria are still maturing. Long-term oncologic safety of watch-and-wait after ICIs: early outcomes are excellent in series, but large, long follow-up datasets are still limited. Best regimen for pMMR/MSS LARC: Which combination (LCRT+ICI vs SCRT+chemo+ICI vs TNT+ICI), which sequencing, and which patients truly benefit remains an open field. Biomarkers beyond MSI/MMR (microbiome, immune microenvironment, novel checkpoints) are promising but not ready for routine perioperative decision-making. Bottom line for clinicians This Gut 2026 CNSCRS consensus converts a fast-moving evidence base into a workable clinical playbook: test MSI/MMR upfront, decide in MDT, use ICIs decisively in dMMR/MSI-H LARC (including structured organ preservation when cCR is achieved), and approach pMMR/MSS strategies with selection, vigilance, and trial-minded discipline.

SCREESCO Trial: Colonoscopy + FIT and Early CRC Detection? Nature Medicine | February 2026

The SCREESCO randomised controlled trial provides rare population-level evidence comparing primary colonoscopy, low-threshold faecal immunochemical testing (FIT), and usual care in colorectal cancer (CRC) screening. Over 278,000 Swedish adults aged 60 years were randomised and followed for nearly five years during the diagnostic phase. During this early period, overall CRC incidence was similar between colonoscopy and usual care, and slightly lower in the FIT arm. However, both screening strategies detected significantly more stage I–II cancers compared with controls—particularly colonoscopy—suggesting a stage shift toward earlier diagnosis rather than immediate reduction in overall incidence. Adverse events were modestly increased in the first year among screened participants, including gastrointestinal and cardiovascular events, but differences attenuated over time. Participation rates were 35% for colonoscopy and 55% for FIT, highlighting real-world uptake challenges. These findings emphasise that the early benefit of CRC screening lies in increased detection of localised disease, while harms appear small and largely front-loaded. Long-term follow-up will determine whether this stage shift translates into reduced CRC mortality. Clinical Implication: Both colonoscopy and FIT enhance early cancer detection, but participation, safety balance, and long-term mortality outcomes remain central to screening policy decisions.

Chemotherapy-Only Neoadjuvant Strategy in High-Risk Rectal Cancer- BJS Open Feb.26

This multicentre phase II Japanese trial evaluated a chemotherapy-only neoadjuvant approach—FOLFOXIRI plus bevacizumab without radiotherapy—for MRI-defined high-risk locally advanced rectal cancer (LARC). Thirty-one patients with at least one high-risk feature (cT4 disease, mesorectal fascia involvement, extramural vascular invasion, or lateral pelvic lymph node metastasis) received four cycles of FOLFOXIRI plus bevacizumab followed by two cycles of FOLFOXIRI before total mesorectal excision. All patients proceeded to surgery. The pathological complete response (pCR) rate was modest at 10%, but the R0 resection rate was high (97%), indicating strong local resectability. At a median follow-up of nearly 3 years, local recurrence was low (3%), with 3-year recurrence-free survival and overall survival of 73% and 81%, respectively. Toxicity was manageable: grade ≥3 neutropenia occurred in 29%, and grade ≥III postoperative complications in 23%, including 7% anastomotic leak. Notably, no gastrointestinal perforations were observed. Although the pCR rate was lower than that of typical chemoradiotherapy-based regimens, the study suggests that intensive systemic chemotherapy may achieve good local control in selected high-risk patients. This strategy could be considered in patients unsuitable for pelvic radiotherapy, but larger comparative trials are needed before broader adoption.

Pan-Tumour Pathologic Response Guidelines Standardise Neoadjuvant Assessment Across Cancers - ASCPO Post

As neoadjuvant therapy expands across tumor types, pathologic response after surgery is increasingly used as a predictor of long-term survival and as a key clinical trial endpoint. However, response scoring systems have historically varied by tumor type, creating inconsistency in reporting and limiting cross-trial comparisons. A joint effort by the Society for Immunotherapy of Cancer (SITC) and the International Neoadjuvant Melanoma Consortium has now produced the first unified, pan-tumor framework for assessing pathologic response to neoadjuvant therapy. The updated consensus guidelines harmonize evaluation across cancer types by focusing on three core components: percentage of residual viable tumor, necrosis, and regression in both primary tumor and lymph nodes. The guidelines also standardize tissue sampling. Tumors ≤3 cm should be submitted entirely for embedding; larger tumors require at least one full cross-section from the longest dimension, including the tumor–host interface when feasible. A multi-institutional reproducibility study demonstrated strong interobserver agreement among trained pathologists across 12 tumor types, supporting reliability of the unified approach. Correlation coefficients exceeded 0.8 for all key measures. This harmonised system simplifies reporting, enhances comparability across studies, and may facilitate future regulatory use of pathologic response endpoints. Ongoing efforts aim to refine tumor-specific response thresholds while maintaining the overarching standardized framework.

Exercise Boosts Anticancer Immunity via Gut Microbiome Formate- Gastroenterology Feb.26

Introduction Physical exercise has long been associated with better cancer outcomes and improved response to immune checkpoint inhibitors (ICIs). Separately, the gut microbiome is now known to influence ICI efficacy. What has been missing is a direct mechanistic bridge connecting these two observations. This work provides that missing link: exercise alters the gut microbiome, which produces metabolites that directly enhance antitumor CD8 T-cell immunity—and can improve immunotherapy response in preclinical models. Problem statement We have strong associations: Exercise → improved cancer outcomes, microbiome composition → ICI response. But until now, it was unclear whether: Exercise benefits are caused by microbiome changes, and whether specific microbial metabolites drive the immune effects. What the study did: Using a melanoma mouse model resistant to ICIs, researchers compared: exercised mice (treadmill + wheel running) vs sedentary mice. They then tested causality by: transferring faecal microbiota from exercised vs sedentary mice, using antibiotics, germ-free mice, and co-housing, and separating the effects of live bacteria vs sterile-filtered metabolites. Finally, they identified a candidate metabolite and validated it through: oral supplementation experiments, bacterial genetics (a formate-producing enzyme knockout), and human donor FMT stratified by formate production. Key findings clinicians should understand 1) Exercise strengthens antitumor immunity—CD8 T cells are essential Exercise restrained tumour growth and enhanced CD4/CD8 function. When lymphocytes were absent, the benefit disappeared, pinpointing adaptive immunity—especially CD8 cells—as the key effector. 2) The gut microbiome is a causal mediator (not just a bystander) Faecal microbiota transplantation (FMT) from exercised mice transferred the antitumor benefit to sedentary mice, improving tumour control and cytotoxic CD8 (Tc1) responses. Antibiotics and germ-free conditions removed the benefit, reinforcing that microbes are required. 3) The “active ingredient” is microbial metabolites, not just bacteria Heat-killed faeces lost the effect. Sterile-filtered faecal metabolites preserved it. That strongly suggests metabolites produced by live bacteria are the functional mechanism. 4) A single metabolite stood out: formate Exercise increased formate levels systemically and in the tumor environment. Higher formate tracked with better tumour control and stronger Tc1 activity. 5) Formate can reproduce the benefit if adaptive immunity is intact Oral formate supplementation limited tumor progression and prolonged survival, but only when adaptive immunity was present. 6) Mechanism: formate activates Nrf2 in CD8 T cells Formate enhanced CD8 T-cell proliferation and cytotoxic function through Nrf2 activation. Blocking or deleting Nrf2 eliminated benefits; an Nrf2 agonist reproduced them. 7) Translational signal: human “high-formate” microbiomes mattered FMT from human donors with high formate production promoted stronger antitumor immunity in mice compared with low-formate donors—suggesting a plausible human-relevant axis. Clinical interpretation This is not a “go prescribe formate” clinical recommendation yet. It is a strong mechanistic proof-of-concept: Exercise may improve antitumor immunity partly by shifting the microbiome toward formate-producing metabolism. Formate behaves like a postbiotic capable of enhancing CD8 T-cell function. The microbiome’s metabolic output (not just taxonomy) may help explain variable immunotherapy responses. Bottom-line takeaway: Exercise enhances anticancer immunity through a microbiome-derived metabolite—formate—which activates Nrf2 in CD8 T cells and boosts cytotoxic antitumor function. This opens a credible path toward combined strategies: exercise + microbiome modulation + metabolite-based “postbiotics” to augment immunotherapy. One-line GastroAGI takeaway Exercise may “train” immunity through the gut microbiome—via formate-driven CD8 activation.