Targeting Glucose Metabolism to Enhance Immunotherapy: Emerging Evidence on Intermittent Fasting and Calorie Restriction Mimetics

Abstract

There is growing interest in harnessing lifestyle and pharmaceutical interventions to boost immune function, reduce tumor growth, and improve cancer treatment efficacy while reducing treatment toxicity. Interventions targeting glucose metabolism are particularly promising, as they have the potential to directly inhibit tumor cell proliferation. However, because anti-tumor immune effector cells also rely on glycolysis to sustain their clonal expansion and function, it remains unclear whether glucose-modulating therapies will support or hinder anti-tumor immunity. In this perspective, we summarize a growing body of literature that evaluates the effects of intermittent fasting, calorie restriction mimetics, and anti-hyperglycemic agents on anti-tumor immunity and immunotherapy outcomes. Based on the limited data currently available, we contend that additional pre-clinical studies and clinical trials are warranted to address the effects of co-administration of anti-hyperglycemic agents or glucose-lowering lifestyle modifications on anti-tumor immunity and cancer treatment outcomes. We stress that there is currently insufficient evidence to provide recommendations regarding these interventions to cancer patients undergoing immunotherapy. However, if found to be safe and effective in clinical trials, interventions targeting glucose metabolism could act as low-cost combinatorial adjuvants for cancer patients receiving immune checkpoint blockade or other immunotherapies.

Manipulation of Glucose Availability to Boost Cancer Immunotherapies

“…As we will discuss throughout this review, targeting glucose metabolism concomitantly provides an opportunity to improve the longevity of the anti-tumor T cell response and to contrast tumor growth, thus representing a therapeutic option to be contemplated in immunotherapeutic strategies. Nonetheless, considering that T cells rely on glucose metabolism for their activation, glucose-modulating therapies may concomitantly support and hamper anti-tumor immunity [ 9 ], suggesting that predictive biomarker-based approaches should be implemented. Moreover, potential side effects, off-target effects, and the complexity of the whole-body metabolism can interfere with the effectiveness of a metabolic manipulation in cancer settings.…”

Nanoengineered targeting strategy for cancer immunotherapy

“…These changes lead to functional programming in TAMs, including the production of cytokines and angiogenetic factors, and result in tumor progression and metastasis. Consumption of the energy sources (e.g., glucose) can support tumor growth, and the glucose metabolism product lactate is an important immunosuppressive metabolite in the tumor microenvironment and a driving factor for TAM-2 polarization [69]. In addition, the hypoxia and low pH of the tumor microenvironment can hinder antitumor immune responses of tumor-infiltrating T cells by limiting nutrient and energy consumption [70].…”

Sodium-Dependent Glucose Transporter 1 (SGLT1) Stabled by HER2 Promotes Breast Cancer Cell Proliferation by Activation of the PI3K/Akt/mTOR Signaling Pathway in HER2+ Breast Cancer

“…Consequently, the identification of novel molecular and genetic biomarkers for diagnosis, prognostic estimation, and therapeutic targets for HER2+ breast cancer patients is necessary. Recent studies have revealed that a series of metabolic alterations, especially in glucose metabolism, allow cancer cells to acquire more nutrients and energy to promote rapid proliferation and metastasis [37,38]. Previous studies have also reported that SGLT1 is highly expressed in various malignant tumor cells of epithelial origin.…”