In recent years, the fasting-mimicking diet (FMD) has emerged as a notable strategy in the field of clinical oncology, particularly for its potential to impact tumor growth and alter immune responses. This dietary approach aims to mimic the physiological effects of fasting without the need for complete food deprivation. Its relevance in cancer treatment revolves around the understanding of how caloric restriction can induce metabolic adaptations that may inhibit tumor progression while simultaneously enhancing the host’s immune system. Among the different immune cell populations within the tumor microenvironment, tumor-associated macrophages (TAMs) play a pivotal role in influencing tumor behavior, and their responses to nutritional interventions like FMD are less understood.
Recent studies have highlighted the need for an in-depth investigation into how FMD influences TAM functionalities. TAMs can either support tumor survival and growth or activate anti-tumor immunity, owing to their plasticity. Understanding the molecular mechanisms behind FMD’s effects on TAMs could open up new avenues for therapeutic interventions. A significant area of interest is the ubiquitin-proteasome system (UPS), known for its role in regulating protein degradation and turnover within cells. Fasting has been shown to activate the UPS, leading to an enhanced ability of cells to manage metabolic stresses.
Intriguingly, the Nuclear Factor Erythroid 2-like 1 (NRF1) has gained attention for its potential to mediate changes in gene expression associated with the proteasome. NRF1 is responsible for the transcription of several genes related to the UPS. Examining how NRF1 function might be altered by diets mimicking fasting could reveal critical insights into its role in TAMs during the immune response to cancer. The hypothesized relationship between FMD, NRF1 activity, and the metabolic fate of TAMs suggests a novel mechanism by which caloric restriction could engage immune cells in a manner that promotes anti-tumor immunity.
This research builds on the foundation laid by previous findings that fasting can enhance the immune surveillance mechanisms against tumors. Not only does fasting alter metabolic pathways, but it also modifies the signaling networks that govern immune cell behavior. The induction of NRF1 by fasting or FMD may serve as a central mechanism through which protein turnover is regulated in TAMs, subsequently influencing their capacity to secrete key cytokines like interferon-beta (IFNβ). IFNβ is known for its role in establishing antiviral responses and modulating immune cell functions, making its secretion an important factor in the context of tumor immunity.
The study proposes that the metabolic reprogramming induced by FMD contributes to an increased secretion of IFNβ from TAMs through NRF1-mediated pathways. This raises essential questions about the interplay between dietary practices and immune regulation in the context of cancer treatment. Does the caloric restriction inherent in FMD truly recast the roles of TAMs from tumor promoters to tumor suppressors? Can nutritional interventions be systematically integrated into oncological care to enhance therapeutic responses?
As researchers embark on this intriguing avenue of study, they employ various experimental techniques to unravel the complexities of how FMD impacts cellular behaviors within the tumor microenvironment. Cellular assays, proteomic analyses, and in vivo models will provide substantial data on the expression patterns of NRF1 and the downstream effects on protein metabolism in TAMs under altered nutritional states. The potential for using FMD as an adjunct therapy opens the door to integrative cancer treatment approaches that prioritize not only the direct targeting of tumors but also the supportive modulation of host immune functions.
Moreover, exploring the connections between dietary habits and cancer biology underscores the profound implications of lifestyle choices on health outcomes. As investigations continue, the hope is that findings will not only define the mechanistic pathways driven by FMD but also address how these mechanisms can be leveraged in clinical settings. By optimizing the timing and composition of dietary interventions, oncologists may be able to synergize the effects of pharmacological treatments with those of nutrition, thus broadening the scope of personalized medicine.
Emerging insights into the relationship between fasting, immune modulation, and tumor behavior mark a promising frontier in cancer research. The intricate link between macronutrient availability, immune dynamics, and tumor microenvironment composition poses new questions about how to effectively harness the body’s own biological systems in the fight against cancer. Identifying the molecular players involved in these processes as defined in the context of FMD is crucial for advancing treatment methodologies.
Furthermore, the potential applicability of FMD in managing therapeutic side effects and improving the quality of life for cancer patients remains a critical consideration. As researchers delve deeper into this promising nexus of nutrition and oncology, the ultimate goal remains: to uncover practical guidelines that could lead to a clearer understanding of how dietary strategies can optimize cancer therapy and promote long-term survival.
In conclusion, the study’s focus on the newly discovered roles of NRF1 in modulating the immune response of TAMs under FMD conditions represents a pivotal step in bridging the gap between nutritional science and clinical oncology. Future studies and clinical trials will need to validate the proposed mechanisms and assess the efficacy of FMD as a viable adjunct to existing cancer therapies, reinforcing the notion that our approach to cancer treatment may benefit from a broader perspective that includes dietary elements as powerful tools for enhancement of host immunity.
Subject of Research: Impact of fasting-mimicking diet on tumor-associated macrophages and their anti-tumor immunity mediated by NRF1.
Article Title: Fasting-mimicking diet induces IFNβ secretion in tumor-associated macrophages via NRF1-mediated ubiquitin-dependent proteolysis of Trex1.
Article References:
Li, J., Jiang, W., Tu, G. et al. Fasting-mimicking diet induces IFNβ secretion in tumor-associated macrophages via NRF1-mediated ubiquitin-dependent proteolysis of Trex1. Br J Cancer (2026). https://doi.org/10.1038/s41416-025-03319-4
Image Credits: AI Generated
DOI: 10.1038/s41416-025-03319-4
Keywords: fasting-mimicking diet, tumor-associated macrophages, NRF1, immune modulation, cancer therapy, ubiquitin-proteasome system, interferon-beta, metabolic reprogramming.
