Metabolic alterations have been observed in many cancer types. The deregulated metabolism has thus become an emerging hallmark of the disease, where the metabolism is frequently rewired to aerobic glycolysis. This has led to the concept of "metabolic reprogramming", which has therefore been extensively studied. Over the years, it has been characterized the enhancement of aerobic glycolysis, where key mutations in some of the enzymes of the TCA cycle, and the increased glucose uptake, are used by cancer cells to achieve a "metabolic phenotype" useful to gain a proliferation advantage. Many studies have highlighted in detail the signaling pathways and the molecular mechanisms responsible for the glycolytic switch. However, glycolysis is not the only metabolic process that cancer cells rely on. Oxidative Phosphorylation (OXPHOS), gluconeogenesis or the beta-oxidation of fatty acids (FAO) may be involved in the development and progression of several tumors. In some cases, these metabolisms are even more crucial than aerobic glycolysis for the tumor survival. This review will focus on the contribution of these alterations of metabolism to the development and survival of cancers. We will also analyze the molecular mechanisms by which the balance between these metabolic processes may be regulated, as well as some of the therapeutical approaches that can derive from their study.

Ubiquitination is a post-translational modification that targets specific proteins on their lysine residues. Depending on the type of ubiquitination, this modification ultimately regulates the stability or degradation of the targeted proteins. Ubiquitination is mediated by three different classes of enzymes: the E1 ubiquitin-activating enzymes, the E2 ubiquitin-conjugating enzymes and, most importantly, the E3 ubiquitin ligases. E3 ligases are responsible for the final step of the ubiquitin cascade, interacting directly with the target proteins. E3 ligases can also be involved in DNA repair, cell cycle regulation and response to stress; alteration in their levels can be involved in oncogenic transformation and cancer progression. Of all the six hundred E3 ligases of the human genome, only three of them are specific to the mitochondrion: MARCH5, RNF185 and MUL1. Their alterations (that reflect on the alteration of the mitochondria functions) can be related to cancer progression, as underlined by the increasing research performed in recent years on these three mitochondrial enzymes. This review will focus on the function and mechanisms of the mitochondrial E3 ubiquitin ligases, as well as their important targets, in cancer development and progression, also highlighting their potential use for cancer therapy.

The identification of new therapeutic targets and the development of innovative therapeutic approaches are the most important challenges for osteosarcoma treatment. In fact, despite being relatively rare, recurrence and metastatic potential, particularly to the lungs, make osteosarcoma a deadly form of cancer. In fact, although current treatments, including surgery and chemotherapy, have improved survival rates, the disease’s recurrence and metastasis are still unresolved complications. Insights for analyzing the still unclear molecular mechanisms of osteosarcoma development, and for finding new therapeutic targets, may arise from the study of post-translational protein modifications. Indeed, they can influence and alter protein structure, stability and function, and cellular interactions. Among all the post-translational modifications, ubiquitin-like modifications (ubiquitination, deubiquitination, SUMOylation, and NEDDylation), as well as glycosylation, are the most important for regulating protein stability, which is frequently altered in cancers including osteosarcoma. This review summarizes the relevance of ubiquitin-like modifications and glycosylation in osteosarcoma progression, providing an overview of protein stability regulation, as well as highlighting the molecular mediators of these processes in the context of osteosarcoma and their possible targeting for much-needed novel therapy.

Cancer metabolism underwent a conceptual revolution over the past decade. Research has long focused on aerobic glycolysis, but recently a more nuanced view is emerging. Tumors dynamically switch among different metabolic pathways, from oxidative phosphorylation to glutaminolysis and β-oxidation. Those metabolic alterations lead to increased growth and therapy resistance.Nevertheless, these alterations are not solely cell-autonomous. The tumor microenvironment (TME) acts as an active metabolic ecosystem, in which immune, stromal, and endothelial cells influence and respond to tumor metabolic demands.The cross-talk between immunity and metabolism, referred to as immunometabolism, determines how tumors evade immune surveillance or how immune activation reshapes cancer metabolism. This Special Issue in Frontiers in Immunology brings together five papers (three reviews and two original research articles) exploring these interconnections across diverse malignancies, from squamous and lymphoid cancers to lung and laryngeal carcinomas. These studies provide insight into how metabolism cues within the TME-sculpt immune function and influence cancer fate.In their review, Qinyi Dong and Lili Liang analyze cutaneous squamous cell carcinoma (cSCC) as a paradigm of immune dysregulation within a metabolically altered TME. They highlight how UV-induced mutagenesis and chronic inflammation generate a immunosuppressive niche dominated by regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Mechanistic insight into the PD-L1/PD-1 and TGF-β/Smad pathways reveals how these axes integrate metabolic stress with immune escape. The review also summarizes clinical data on immune checkpoint inhibitors, including the monoclonal antibodies cemiplimab and pembrolizumab. The authors propose future strategies, including combinatorial and vaccine-based immunotherapy, tailored to the metabolic and immune profile of cSCC.Chengqian Chen and colleagues provide a review on the metabolic-immune axis in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). They emphasize that enhanced glycolysis and amino acid metabolism fuel tumor growth, but concurrently shape an immunosuppressive milieu via lactate accumulation, nutrient competition, and checkpoint evasion, with a molecular network involving PD-L1, LAG-3, and TIM-3. Their synthesis of PET-based metabolic imaging and immune profiling data demonstrates that integrating metabolic and immune biomarkers refines prognostic stratification and supports the rational combination of metabolic inhibitors with immunotherapy. This represents an important step toward precision lymphoma management.Jiayi Dong et al. propose a review focusing on drug functional remapping as a strategic approach to accelerate the development of cancer immunotherapy. By reanalyzing clinically approved drugs, the authors reveal how these agents may reprogram immune metabolism or counteract checkpoint inhibitor resistance. This review also surveys computational and high-throughput screening tools enabling systematic repurposing. The result is a compelling case for expanding therapeutic discovery beyond de novo drug development, using immunometabolic principles to reposition well-characterized compounds for cancer treatment.Gen Li and colleagues identify fibrinogen alpha chain (FGA) as a suppressor of lung adenocarcinoma (LUAD) progression by modulating of SLC7A11/xCT-mediated disulfidptosis.Using transcriptomic analyses and functional assays, they demonstrate that FGA restrains malignant proliferation and invasion while influencing immune infiltration patterns in the LUAD TME. The study highlights disulfidptosis (a recently described disulfide-stress-induced cell death pathway) as a therapeutic vulnerability that links redox homeostasis to tumor immunity.Dan Zheng and colleagues have combined integrative multi-omics and machine learning to delineate two metabolic subtypes of laryngeal cancer (LCA), with distinct prognoses and immune features. The LCA1 subtype exhibits enhanced metabolic pathway enrichment and NSD1 mutations, both of which are associated with improved outcomes. On the other hand, the LCA2 subtype shows higher immune infiltration and checkpoint expression but poorer survival. The diagnostic and prognostic models developed by the authors demonstrate strong predictive performance, reinforcing the clinical potential of metabolic profiling for patient stratification.Across these studies, several unifying themes that reshape our understanding of cancer immunometabolism can be identified. First, the reciprocal regulation between tumor and immune cells, which are metabolically interdependent. Tumor-derived metabolites (lactate, kynurenine, adenosine) modulate immune effector function, while activated immune cells impose metabolic pressure on tumor survival pathways.Moreover, distinct metabolic states coexist within the same tumor, creating spatially and temporally heterogeneous niches that complicate therapy. Integrative -omics and spatial transcriptomic tools are beginning to unravel this complexity, but this will represent an important field of future research.From a therapeutic standpoint, metabolic reprogramming can be leveraged to potentiate immunotherapy. From repurposed metabolic drugs to redox-targeted interventions and metabolic subtype-based treatment design, these strategies promise to overcome resistance and enhance immune efficacy. Analyzing metabolic, immune, and clinical datasets enables predictive modeling of patient outcomes, advancing immunometabolism toward actionable clinical translation.The next frontier in this field lies in dissecting the spatial and temporal organization of metabolic networks within the TME. High-resolution single-cell and spatial metabolomic technologies can now map nutrient fluxes and redox gradients at the cellular level, offering unprecedented insight into local metabolic competition and...