Malignant pleural mesothelioma (MPM) is a lethal and rare cancer, even if its incidence has continuously increased all over the world. Asbestos exposure leads to the development of mesothelioma through multiple mechanisms, including chronic inflammation, oxidative stress with reactive oxygen species (ROS) generation, and persistent aberrant signaling. Together, these processes, over the years, force normal mesothelial cells’ transformation. Chronic inflammation supported by “frustrated” macrophages exposed to asbestos fibers is also boosted by the release of pro-inflammatory cytokines, chemokines, growth factors, damage-associated molecular proteins (DAMPs), and the generation of ROS. In addition, the hypoxic microenvironment influences MPM and immune cells’ features, leading to a significant rewiring of metabolism and phenotypic plasticity, thereby supporting tumor aggressiveness and modulating infiltrating immune cell responses. This review provides an overview of the complex tumor–host interactions within the MPM tumor microenvironment at different levels, i.e., soluble factors, metabolic crosstalk, and oxidative stress, and explains how these players supporting tumor transformation and progression may become potential and novel therapeutic targets in MPM.

Malignant melanoma represents the most fatal skin cancer due to its aggressive behavior and high metastatic potential. The introduction of BRAF/MEK inhibitors and immune-checkpoint inhibitors (ICIs) in the clinic has dramatically improved patient survival over the last decade. However, many patients either display primary (i.e., innate) or develop secondary (i.e., acquired) resistance to systemic treatments. Therapeutic resistance relies on the rewiring of multiple processes, including cancer metabolism, epigenetics, gene expression, and interactions with the tumor microenvironment that are only partially understood. Therefore, reliable biomarkers of resistance or response, capable of facilitating the choice of the best treatment option for each patient, are currently missing. Recently, activation of nicotinamide adenine dinucleotide (NAD) metabolism and, in particular, of its rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT) have been identified as key drivers of targeted therapy resistance and melanoma progression. Another major player in this context is the mammalian target of rapamycin (mTOR) pathway, which plays key roles in the regulation of melanoma cell anabolic functions and energy metabolism at the switch between sensitivity and resistance to targeted therapy. In this review, we summarize known resistance mechanisms to ICIs and targeted therapy, focusing on metabolic adaptation as one main mechanism of drug resistance. In particular, we highlight the roles of NAD/NAMPT and mTOR signaling axes in this context and overview data in support of their inhibition as a promising strategy to overcome treatment resistance.

Breast cancer stands as a primary malignancy among women, ranking second in global cancer-related deaths. Despite treatment advancements, many patients progress to metastatic stages, posing a significant therapeutic challenge. Current therapies primarily target cancer cells, overlooking their intricate interactions with the tumor microenvironment (TME) that fuel progression and treatment resistance. Dysregulated innate immunity in breast cancer triggers chronic inflammation, fostering cancer development and therapy resistance. Innate immune pattern recognition receptors (PRRs) have emerged as crucial regulators of the immune response as well as of several immune-mediated or cancer cell-intrinsic mechanisms that either inhibit or promote tumor progression. In particular, several studies showed that the Toll-like receptor 2 (TLR2) and the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathways play a central role in breast cancer progression. In this review, we present a comprehensive overview of the role of TLR2 and STING in breast cancer, and we explore the potential to target these PRRs for drug development. This information will significantly impact the scientific discussion on the use of PRR agonists or inhibitors in cancer therapy, opening up new and promising avenues for breast cancer treatment.

Cancer cells adapt to microenvironmental cues through the coordinated integration of metabolic reprogramming, epigenetic remodeling, and immune regulation. An emerging central regulator of this adaptive network is coordinated nicotinamide metabolism, which controls both nicotinamide adenine dinucleotide (NAD) biosynthesis and cellular methylation potential. Within this network, the nicotinamide-metabolizing enzymes nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide N-methyltransferase (NNMT) govern the metabolic fate of nicotinamide (NAM), thereby coupling energy metabolism to epigenetic regulation and adaptive cellular responses. NAMPT, the rate-limiting enzyme of the NAD salvage pathway, sustains intracellular NAD pools required for redox homeostasis, mitochondrial function, DNA repair, and stress responses. Conversely, NNMT diverts NAM from NAD biosynthesis by catalyzing its methylation while consuming S-adenosylmethionine (SAM), thereby creating a methylation sink that remodels chromatin organization and promotes transcriptional plasticity. Beyond intracellular metabolism, coordinated nicotinamide metabolism extends to the tumor microenvironment through extracellular mediators, including extracellular NAMPT (eNAMPT), the emerging extracellular functions of NNMT (eNNMT) and its metabolite 1-methylnicotinamide (1-MNA), which regulate stromal remodeling, immune cell function, chronic inflammation, and immune evasion. Collectively, these complementary intracellular and extracellular activities establish a multilevel adaptive network that integrates metabolic homeostasis, epigenetic remodeling, and immunometabolic communication, thereby promoting tumor plasticity, therapeutic adaptation, and resistance. Here, we propose a conceptual framework in which NAMPT and NNMT function as complementary regulators of coordinated nicotinamide metabolism operating across interconnected intracellular and extracellular levels. By integrating metabolic, epigenetic, and immune crosstalk into a unified model of tumor adaptation, this perspective provides new insights into tumor progression and therapy resistance while highlighting context-dependent opportunities for mechanism-based combination therapies in cancer.

Chronic inflammation is a major driver of lung damage in cystic fibrosis (CF), yet the molecular mechanisms that sustain this self-reinforcing inflammatory state remain incompletely understood. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD biosynthesis, can also act extracellularly (eNAMPT) as a pro-inflammatory mediator. Here, we investigated the relationship between NAMPT and matrix metalloproteinase-9 (MMP-9) in CF. Peripheral blood mononuclear cells (PBMCs) from people with CF (pwCF) displayed increased intracellular NAMPT and MMP-9 expression, together with enhanced AKT and ERK1/2 phosphorylation, compared with non-CF controls. Circulating eNAMPT levels were elevated in pwCF and positively correlated with MMP-9 levels. Although baseline eNAMPT levels were not significantly associated with FEV1% predicted, in a small longitudinal cohort, eNAMPT decreased following one year of elexacaftor/tezacaftor/ivacaftor (ETI) treatment, while FEV1% predicted increased in six of seven patients with paired measurements. In vitro, recombinant NAMPT increased MMP-9 expression and enzymatic activity in PBMCs from healthy donors. Pharmacological treatment with FK866 reduced endogenous eNAMPT release and attenuated NAMPT-induced MMP-9 production. Mechanistically, eNAMPT triggered rapid AKT activation followed by sustained ERK1/2 phosphorylation. Pharmacological inhibition of the MEK/ERK pathway attenuated NAMPT-induced MMP-9 activity, supporting a functional contribution of ERK1/2 signaling to NAMPT-mediated MMP-9 activation. Together, these findings identify a functional NAMPT–MMP-9 axis associated with inflammatory signaling in CF. Further studies are needed to establish its contribution to pulmonary inflammation and to determine the clinical significance of circulating eNAMPT in larger patient cohorts.