Dietary restriction of methionine, an essential amino acid found in protein, can lead to tumor-suppressing or tumor-promoting effects in mice, depending on the status of the immune system, according to recent NIEHS-funded research. The new findings, which highlight the importance of evaluating models of both healthy and weakened immune systems, hold the promise of informing future dietary interventions for cancer therapies. The study was published Aug. 3 in the journal Nature Metabolism.

Methionine restriction has been promoted as an effective dietary regimen to control various conditions, including cancer. However, results from the study, led by Ming Ji, Ph.D., a research fellow, showed that in mice with healthy immune systems, or immunocompetent mice, such restriction impairs the immune system’s ability to control tumor growth, partially through gut microbes.

“We believe the discoveries we made in this study reflect the intricate trade-off between tumor-promoting and immune-activating impacts of methionine, which is intrinsically context dependent,” said senior study author Xiaoling Li, Ph.D., who leads the Metabolism, Genes, and Environment Group. “Our study suggests that any possible anticancer benefits of methionine restriction require careful consideration of both the microbiota and the immune system.”

Essential but enigmatic

Methionine, a sulfur-containing essential amino acid, is a key component of dietary proteins that are important for protein synthesis, sulfur metabolism, antioxidant defense, signaling, and overall cellular functions. But the role of methionine in regulating cancer progression remains inconclusive.

On the one hand, many cancer cells highly depend on methionine. Dietary restriction of methionine represses the proliferation and progression of various tumors and improves therapeutic responses in several preclinical cancer models, most of which were conducted using mice with weakened immune systems.

On the other hand, methionine is critical for T cell activation that is essential for immunity. It is, therefore, a potential tumor-suppressing nutrient that boosts T cell-mediated antitumor immunity.

“In light of these conflicting findings, it has not been clear how methionine restriction impacts cancer progression in the context of the intact immune system,” Li said.

Interaction with immunity

To address this knowledge gap, Li and her team investigated the interaction between dietary methionine, immune cells, and cancer cells in mice that had either intact or deficient immune systems. The results showed that methionine restriction inhibited cancer growth in immunocompromised mice, which are mice with deficient or weakened immune systems. But in immunocompetent mice with healthy immune systems, the dietary regimen reduced T-cell abundance, exacerbated tumor growth, and impaired tumor response to immunotherapy.

“This discovery is clinically important and potentially paradigm shifting, as it suggests that in the clinical setting, methionine restriction may be beneficial for the treatment of immunocompromised cancer patients, but will be detrimental to immunocompetent individuals, particularly at the early stage when antitumor immunity is pivotal for containing tumors,” Li said.

“Conversely, dietary methionine supplementation may boost antitumor immunity in immunocompetent individuals, but will support tumor growth in immunocompromised cancer patients,” she continued. “We believe this distinction may be critical for the success of clinical dietary interventions for cancer.”

Microbes and methionine

Additional experiments uncovered a vital role of gut microbes in mediating the impact of methionine restriction on cancer in immunocompetent mice (see sidebar). Specifically, methionine restriction led to a deficiency in microbial production of hydrogen sulfide, which is critical for immune cell survival and activation. Consistent with these findings, dietary methionine supplementation enhanced antitumor immunity and suppressed tumor growth partially through the gut microbiota.

“This finding raises an exciting possibility that microbial engineering may help to boost the efficacy of antitumor immunotherapies,” Li said.

The next step, according to Li, is to validate these findings in humans, potentially paving the way to novel strategies for cancer therapies.

“Additional studies are needed to pinpoint the best therapeutic windows in immunocompetent individuals for both methionine restriction and methionine supplementation,” Li said. “Moreover, although our study highlighted the importance of gut microbial hydrogen sulfide in promoting immune cell survival and activation, additional studies are required to better understand the underlying molecular mechanisms.”