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In recent years, mostly spanning the past decade, the concept of immunometabolism has ushered with a novel perspective on carcinogenesis, tumor progression, and tumor response to therapy. It has become clear that the metabolic state of immune cells plays a significant role in shaping their antitumor or protumor activities within the cancer microenvironment. Consequently, the examination of tumor metabolic heterogeneity, including an exploration of immunometabolism, proves indispensable for enhancing prognostic tools and advancing the quest for personalized treatments. Here we have delved into how metabolic reprogramming profoundly influences the acquisition and maintenance of functional states, spanning from effector and cytotoxic profiles to regulatory and immunosuppressive phenotypes in both innate and adaptive immunity. These alterations wield considerable influence over tumor evolution and affect the outcome of cancer. Furthermore, we explore some of the cellular signaling mechanisms that underpin the metabolic and phenotypic flexibility of immune cells in response to external stimuli. Show less

Non‑small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite significant advances in targeted therapy and immunotherapy, the overall prognosis of patients with NSCLC remains poor. Hypoxia is a critical driving factor in tumor progression, influencing the biological behavior of tumor cells through complex molecular mechanisms. The present review systematically examined the role of the hypoxic microenvironment in NSCLC, demonstrating its crucial role in promoting tumor cell growth, invasion and metastasis. Additionally, it has been previously reported that the hypoxic microenvironment enhances tumor cell resistance by activating hypoxia‑inducible factor and regulating exosome secretion. The hypoxic microenvironment also enables tumor cells to adapt to low oxygen and nutrient‑deficient conditions by enhancing metabolic reprogramming, such as through upregulating glycolysis. Further studies have shown that the hypoxic microenvironment facilitates immune escape by modulating tumor‑associated immune cells and suppressing the antitumor response of the immune system. Moreover, the hypoxic microenvironment increases tumor resistance to radiotherapy, chemotherapy and other types of targeted therapy through various pathways, significantly reducing the therapeutic efficacy of these treatments. Therefore, it could be suggested that early detection of cellular hypoxia and targeted therapy based on hypoxia may offer new therapeutic approaches for patients with NSCLC. The present review not only deepened the current understanding of the mechanisms of action and role of the hypoxic microenvironment in NSCLC but also provided a solid theoretical basis for the future development of precision treatments for patients with NSCLC. Show less

BackgroundAntioxidant supplements are widely used during cancer treatment to prevent oxidative stress, reduce treatment toxicities, and improve patient outcomes. However, current literature reveals significant gaps suggesting that antioxidants may protect both healthy and tumor cells from oxidative damage, thereby reducing treatment efficacy. It is for this reason that antioxidant supplements have become a source of therapeutic controversy.ObjectiveTo review therapeutic controversies over the use of antioxidant supplements during cancer treatment.MethodsScoping review of the international published articles following the Arksey and O’Malley framework, cross-sectional studies, clinical and pre-clinical studies, systematic and umbrella reviews and grey literatures published from 2014 to 2024 with all age patient populations were included. A structured literature search was conducted of CINAHL, EMBASE, MEDLINE, Google Scholar, using key medical subject heading words and Cochrane Collaboration and Joanna Briggs Institute databases. All included studies were reviewed independently by two investigators. Data were extracted, collated by type of antioxidants, summarized in tables and synthesized for analysis.ResultA total of 1, 550 articles were identified. After reviewing all literatures, twenty-one (21) were full-text articles, grey literatures (2), and systematic reviews (42) and umbrella reviews (3), met the criteria for inclusion. In this review, the use of antioxidant supplements can benefit cancer cells in the same way as they do for normal cells during cancer treatment. In addition, not all antioxidants were effective in inhibiting oxidative stress, reduce treatment toxicities, and improve patient outcomes.Conclusion and recommendationsAccording to this review, the use of antioxidant supplements can benefit tumor cells in the same manner as they do for normal cells. Therefore, oncologists should advise not to take antioxidant supplements during chemotherapy and/or radiotherapy. Future research including potential clinical and preclinical trials, mechanistic studies, and exploration of different vitamin and mineral supplement studies are required to uncover the complete potential of antioxidant supplements for cancer treatment or determine their safety and effectiveness when used alongside standard cancer treatments. Furthermore, the results of this review could be used for future systematic review of therapeutic controversies over use of antioxidant supplements during cancer treatment. Show less

NRF2 (nuclear factor erythroid 2-related factor 2) is a master regulator of protective responses in healthy tissues. However, when it is active in tumor cells, it can result in drug resistance. KEAP1, the endogenous NRF2 inhibitor, binds NRF2 and redirects it to proteasomal degradation, so the KEAP1/NRF2 interaction is critical for maintaining NRF2 at a basal level. A number of clinically relevant KEAP1 mutations were shown to disrupt this critical KEAP1/NRF2 interaction, leading to elevated NRF2 levels and drug resistance. Here, we describe a small-molecule NRF2 inhibitor, R16, that selectively binds KEAP1 mutants and restores their NRF2-inhibitory function by repairing the disrupted KEAP1/NRF2 interactions. R16 substantially sensitizes KEAP1-mutated tumor cells to cisplatin and gefitinib, but does not do so for wild-type KEAP1 cells, and sensitizes KEAP1 G333C-mutated xenograft to cisplatin. We developed a BRET2-based biosensor system to detect the KEAP1/NRF2 interaction and classify KEAP1 mutations. This strategy would identify drug-resistant KEAP1 somatic mutations in clinical molecular profiling of tumors. Show less

The study of cancer metabolism is regaining center stage and becoming a hot topic in tumor biology and clinical research, after a period where such kind of experimental approaches were somehow forgotten or disregarded in favor of powerful functional genomic and proteomic studies [...]. Show less