The efficacy of immune checkpoint inhibitors (ICIs) has been linked to the gut microbiota. Landmark studies in mice and humans have demonstrated that certain commensal bacteria could enhance antitumor immunity and improve ICI response (1, 2). Conversely, microbiome disruption (e.g., by antibiotics) before or during ICI therapy is associated with significantly worse survival outcomes in studies from our institute and others (3, 4). Previously, we had demonstrated that the overall survival of ICI-treated patients with antibiotics decreased by 70% compared with that of patients without antibiotics (4). Furthermore, Turicibacter and Acidaminococcus are the key microbiomes that help determine the clinical efficacy of ICI therapy in study from our institute (5). A recent clinical study in the USA reported that a high dietary fiber intake was correlated with prolonged survival in patients with melanoma receiving ICIs (6). High-fiber diets will promote a diverse (7), beneficial gut microbiome that can augment anticancer immune response (8), despite some opposing views (9, 10).

However, the gut microbiota composition varies greatly across different populations. Notably, the intestinal flora of Japanese individuals—characterized by a high abundance of Bifidobacteria—differs substantially from that of Western populations (11). Dietary habits and nutritional guidelines also differ by region (12), which may influence the microbiota and, in turn, ICI outcomes (13). To date, no study has specifically examined how contemporary Japanese diet patterns might affect the efficacy of ICI therapy. Given these gaps, the present study aimed to investigate whether pretreatment dietary habits in a Japanese patient cohort are associated with the clinical outcomes of ICI therapy. In particular, this study focused on dietary fiber intake—previously identified as beneficial in Western studies—and other diet components prevalent in Japan to identify any “favorite foods” that correlate with better ICI response in the context of Japanese food customs.

To the best of our knowledge, this is the first study to identify a positive association between dietary vinegar intake and ICI therapeutic outcomes. In this Japanese patient cohort, higher consumption of vinegar (acetic acid) was associated with improved tumor response to ICIs, whereas dietary fiber intake showed no significant benefit. These findings highlight the importance of considering regional diet and microbiota differences when evaluating nutritional factors in cancer immunotherapy.

Our hierarchical cluster analysis showed no proximity between vinegar intake and fermented foods intake. This suggests that the effect of vinegar is not a confounding factor of general healthy nutritional behavior. The potential immunological effect of vinegar has only recently begun to gain attention (24). Vinegar has a long history as a folk remedy—dating back to Hippocrates in ancient Greece—being used to treat ailments and clean wounds (25, 26). Contemporary studies are now validating some of the health benefits of vinegar, including its anti-inflammatory and metabolic effects (24, 26). For example, a 2024 study demonstrated that hawthorn vinegar could enhance intestinal immunity and improve general health in an animal model (24). However, the mechanisms by which dietary vinegar might influence anticancer immunity are not fully understood. Broadly, two routes have been hypothesized: (1) indirect effects through modulation of the gut microbiota and its metabolites (25) and (2) direct systemic effects of absorbed acetate on host cells and signaling pathways (27, 28).

1. Microbiota-mediated mechanisms: Short-chain fatty acids (SCFAs) produced by gut bacteria, such as acetate, can modulate immune cell function (29). Acetate, propionate, and butyrate serve as important microbial metabolites that influence both innate and adaptive immunity (13). In particular, acetate enhances IgA production in the colon and affects T-cell differentiation (30). Takeuchi et al. reported that increasing colonic acetate levels increased commensal-specific IgA responses and altered CD4⁺ T-cell activity in mice (30). In patients with cancer on immunotherapy, Nomura et al. found that those with higher fecal concentrations of SCFAs (including acetic acid) had significantly longer PFS than those with low concentrations (31). Thus, acetate in the gut environment may contribute to antitumor immunity, for example, by promoting effector T cells or regulating inflammatory signals.

Could higher dietary intake of vinegar lead to increased colonic acetate levels? Theoretically, ingesting vinegar (acetic acid) might enrich acetate in the colon to fuel these immune-beneficial effects. However, physiological studies have indicated that orally consumed acetate is mostly absorbed in the upper gastrointestinal tract and may not reach the large intestine in substantial amounts (32–35). Sugiyama et al. showed that acetate is rapidly absorbed in the stomach and jejunum (32). In a pig model, portal blood levels of acetic acid rose within 10 min of vinegar ingestion and nearly returned to baseline by 30 min, suggesting that little acetic acid survives to enter the colon (36). Thus, a direct increase of luminal acetate in the colon from drinking vinegar is unlikely. Nonetheless, vinegar could still indirectly affect the composition of the gut microbiota. Recently, Xia et al. reported that consuming traditional aged vinegar altered the gut microbiota in mice, notably increasing beneficial taxa such as Akkermansia (phylum Verrucomicrobia), and reduced intestinal inflammation (37). Another study found that supplementation with Monascus (red yeast) vinegar altered the gut microbiota profile in hyperlipidemic rats, accompanying improvements in lipid metabolism and inflammation (38). Vinegar’s microbial effects were speculated to augment bacterial functions such as oxalate degradation (39). Despite the lack of concrete evidence, regular vinegar intake may subtly shift the gut microbiome toward a community that produces more endogenous acetate or other SCFAs, thereby indirectly bolstering antitumor immunity. Future studies should directly examine the gut microbiome changes in patients consuming vinegar.

2. Systemic mechanisms of vinegar (acetic acid): Acetate readily enters the circulation and can act on various host organs (27, 28, 40). Maslowski et al. (2009) provided a key insight by showing that acetate signaling promoted apoptosis of neutrophils and ameliorated colitis in mice through the GPR43 receptor (41). This indicates that circulating SCFAs can influence immune cell turnover and inflammation resolution. In humans, vinegar consumption confers metabolic benefits such as reducing blood pressure and improving glycemic control (26). A meta-analysis by Shahinfar et al. concluded that vinegar intake produces a dose-dependent reduction in systolic blood pressure (42). It was proposed that acetate suppresses the renin–angiotensin system as demonstrated in spontaneously hypertensive rats (40). Acetate also activates AMP-activated protein kinase (AMPK) and PPARα, leading to increased fatty acid oxidation and reduced body fat in mice (27, 43). In the present study, higher vinegar intake might reflect a diet that includes more fermented or pickled products, which could be linked with an overall healthier metabolic profile (28), potentially supporting better immune function. Okura et al. (44) reported that feeding rats a type of brown rice vinegar enhanced their humoral immune responses (high serum levels of IgA and IgM). Although the exact pathways remain unclear, these findings collectively suggest that acetate can modulate immune and metabolic pathways systemically, independent of the gut microbiota. For cancer immunotherapy, systemic factors such as improved metabolic health or reduced inflammatory tone could translate into a more robust antitumor immune response (13). It is intriguing that mayonnaise (which contains vinegar and fatty acids) also showed a positive association with the ICI response in our univariate screening. One speculation is that SCFAs or other compounds present in these foods might subtly prime the immune system or tumor microenvironment to enhance the responsiveness to ICIs.

In contrast, the inefficacy of dietary fiber in our Japanese cohort prompts the consideration of population differences. Spencer et al. (6) reported that high fiber intake correlates with better ICI outcomes in Western populations, likely by enriching SCFA-producing gut bacteria (13). Why did we not see this in Japan? An obvious reason is that the fiber intake in our patients (median 8 g/day) was substantially lower than in those Western studies, where the median intake was >20 g/day (45). Indeed, the majority of Japanese individuals consume less fiber than the Western-recommended levels. A large Japanese cohort study noted that 80% of the participants had fiber intake <16 g/day (23). This general low-fiber diet could lead to a chronically different gut microbiota. Sonnenburg et al. (46) demonstrated that sustained low-fiber diets over multiple generations of mice caused the extinction of certain gut bacterial species, which could not be fully rescued even after reintroducing fiber. Extrapolating to humans, the contemporarily lower fiber intake in Japan (despite a vegetable-rich diet, the reliance on refined rice as a staple yields lower total fiber) might indicate that Japanese patients start with a gut microbiota of lower diversity and fewer fiber-fermenting bacteria. High microbiota diversity has shown a correlation with better ICI responses; thus, a low-diversity microbiome (as might result from chronically low fiber intake) could be less able to mediate fiber’s benefits on immunity (47). In the present study, even patients who managed to consume ≥20 g/day of fiber did not show improved outcomes, possibly because their microbiome was not primed to convert that fiber into beneficial metabolites. Another factor is the difference in the fiber definition and measurement. Until recently, Japanese food composition tables did not count resistant starch and some oligosaccharides as dietary fiber (17). Thus, a Japanese “20 g” of fiber may actually contain less fermentable substrate than an American “20 g” of fiber. We attempted to account for this by estimating the fermentable fiber but still found no association with the outcomes. It may be that once fiber intake is below a certain threshold (e.g., <15 g/day), its influence on the microbiome and immunity is minimal. In summary, our findings indicate that simply increasing fiber intake did not yield the same immunotherapeutic benefit in a low-fiber–adapted population. Instead, more comprehensive or long-term interventions, such as gradually boosting fiber over generations or directly supplementing beneficial microbes, might be required.

This study has several limitations. First, the sample size was relatively small (n = 32), which limits the statistical power, particularly for survival analyses. Age- and sex-based distribution of the study population was not representative of the broader cancer cohort, limiting generalizability of the results. Variables in multivariable logistic regression were screened using univariate logistic regression without multiple comparison correction. The findings in the presenting study should be interpreted as exploratory and preliminary with great caution. Future studies with larger, more diverse populations are needed to validate these preliminary findings. Second, dietary intake was assessed by FFQ, which is subject to recall bias and provides semiquantitative estimates. The FFQ has been validated using 12-day weighed food records by the developing group; dietary fibers correlated adequately (15); however, the percentage of acetic acid differences are large (−50% to −70%) (16). The FFQ is better at ranking individuals than determining absolute intake; therefore, the intake values should not be taken as precise recommendations. Third, our estimation of fermentable fiber was indirect and did not capture all possible microbiota-accessible carbohydrates (for instance, fiber from fruits, vegetables, and seaweed that might also be fermentable were not separately quantified). No established method currently exists to comprehensively measure fermentable fiber intake in Japan. Fourth, patients’ gut microbiomes were not analyzed. Therefore, microbial mechanisms can be only speculated. The present study cannot explain why the ICI responses were associated with vinegar intake and not dietary fiber intake in the Japanese cohort; concurrent microbiome profiling would strengthen future research. Lastly, although we found an association with vinegar intake, vinegar is still a proxy for some other dietary or lifestyle factors. For example, vinegar intake might correlate with the consumption of certain traditional Japanese dishes or with health-conscious behavior. Controlled intervention studies are needed to confirm the causal effect of vinegar on ICI outcomes.

Despite these limitations, our findings raise interesting possibilities for precision nutrition in cancer immunotherapy. Given the difference in diet–microbiome–immune interactions across regions, the “optimal” diet to support ICI therapy may need to be tailored to local habits. In Western populations, a high-fiber diet is emphasized; however, in Japan, simply advising more fiber might not be effective. Instead, other dietary modifications—such as encouraging fermented foods or vinegar (which are familiar in the Japanese diet)—could be more beneficial adjuncts to therapy. Ultimately, personalized nutritional interventions, designed with consideration of an individual’s microbiota and cultural diet, should be explored as a way to improve ICI efficacy. For instance, a prospective trial could test whether adding a small amount of vinegar (e.g., a tablespoon daily; 15 g/tablespoon, equivalent to acetic acid 750 mg as rice vinegar or apple cider vinegar) (48, 49) to the diet of patients on ICIs improves outcomes compared with a control diet. The safety of drinking vinegar containing 750 mg of acetic acid per 100 mL was also reported (50). Likewise, investigating microbiome changes in such trials would help clarify the mechanism. As the field of immuno-nutrition evolves, what constitutes a “favorable food” during ICI therapy will likely differ between a Japanese patient and a Western patient, and this study underscores the importance of this context-specific approach.

The findings of this study imply that in Japanese patients undergoing ICI therapy, higher vinegar (acetic acid) intake may contribute to a better therapeutic response, whereas dietary fiber intake (at typical Japanese levels) appears to have a limited effect on outcomes. These results underscore that dietary recommendations to enhance ICI efficacy should not adopt a “one-size-fits-all” model but consider regional dietary habits and microbiota profiles. Nutritional interventions that are effective in Western populations may need adaptation in Japan. Integrating modest vinegar consumption into the diet is a feasible approach that could potentially improve ICI responses in Japanese patients; however, further prospective studies are warranted to confirm this benefit. Ultimately, tailoring dietary guidance to individual and ethnic differences—a form of precision nutrition—will be important for optimizing cancer immunotherapy results.