Cancer progression generates a chronic inflammatory state that dramatically influences hematopoiesis, originating different subsets of immune cells that can exert pro- or anti-tumor roles. Commitment towards one of these opposing phenotypes is driven by inflammatory and metabolic stimuli derived from the tumor-microenvironment (TME). Current immunotherapy protocols are based on the reprogramming of both specific and innate immune responses, in order to boost the intrinsic anti-tumoral activity of both compartments. Growing pre-clinical and clinical evidence highlights the key role of metabolism as a major influence on both immune and clinical responses of cancer patients. Indeed, nutrient competition (i.e., amino acids, glucose, fatty acids) between proliferating cancer cells and immune cells, together with inflammatory mediators, drastically affect the functionality of innate and adaptive immune cells, as well as their functional cross-talk. This review discusses new advances on the complex interplay between cancer-related inflammation, myeloid cell differentiation and lipid metabolism, highlighting the therapeutic potential of metabolic interventions as modulators of anticancer immune responses and catalysts of anticancer immunotherapy.

In recent years, the immune system has emerged as a critical regulator of tumor development, progression and dissemination. Advanced therapeutic approaches targeting immune cells are currently under clinical use and improvement for the treatment of patients affected by advanced malignancies. Among these, anti-PD1/PD-L1 and anti-CTLA4 immune checkpoint inhibitors (ICIs) are the most effective immunotherapeutic drugs at present. In spite of these advances, great variability in responses to therapy exists among patients, probably due to the heterogeneity of both cancer cells and immune responses, which manifest in diverse forms in the tumor microenvironment (TME). The variability of the immune profile within TME and its prognostic significance largely depend on the frequency of the infiltrating myeloid cells, which often represent the predominant population, characterized by high phenotypic heterogeneity. The generation of heterogeneous myeloid populations endowed with tumor-promoting activities is typically promoted by growing tumors, indicating the sequential levels of myeloid reprogramming as possible antitumor targets. This work reviews the current knowledge on the events governing protumoral myelopoiesis, analyzing the mechanisms that drive the expansion of major myeloid subsets, as well as their functional properties, and highlighting recent translational strategies for clinical developments.

Despite well-documented metabolic and hematopoietic alterations during tumor development, the mechanisms underlying this crucial immunometabolic intersection remain elusive. Of particular interest is the connection between lipid metabolism and the retinoic acid–related orphan receptor (RORC1/RORγ), whose transcriptional activity modulates cancer-related emergency myelopoiesis and is boosted by cholesterol metabolites, whereas hypercholesterolemia itself is associated with dysregulated myelopoiesis. In this study, we show that cancer and hypercholesterolemic diet independently or cooperatively activate RORγ-dependent expansion of myeloid-derived suppressor cells (MDSC) and M2-polarized tumor-associated macrophages (TAM), supporting cancer spread. Moreover, we report that tumor-induced expression of IL1β and IL6 promotes hepatic expression of proprotein convertase subtilisin/kexin type 9 in preclinical models and patients. Importantly, lowering cholesterol levels, by genetic or pharmacologic inhibition of proprotein convertase subtilisin/kexin type 9, prevents MDSC expansion, M2 TAM accumulation, and tumor progression in a RORγ-dependent manner, unleashing specific antitumor immunity. Overall, we identify RORγ as a key sensor of lipid disorders, bridging hypercholesterolemia and protumor myelopoiesis. Significance: Cancer and a hypercholesterolemic diet independently or collaboratively increase blood cholesterol, which in turn triggers RORγ-dependent expansion of suppressive monocytic MDSCs and M2-like TAMs, thus inhibiting specific antitumor immunity and facilitating disease progression.

The tumor microenvironment (TME) is a highly intricate and dynamic milieu, comprising neoplastic, immune and stromal cells in concert with extracellular matrix components, all engaged in continuous bidirectional crosstalk that critically orchestrates disease progression and therapeutic resistance. Beyond the local context, the TME is deeply shaped also by systemic influences, such as inflammatory mediators, metabolic cues and hematopoietic perturbations, collectively fostering a tumor-permissive macroenvironment. The interplay between local and systemic signals plays a pivotal role in modulating cellular differentiation, immune dynamics and stromal architecture, thereby sustaining malignancy. Among the myriad regulatory modulators involved in this complex network, endogenously produced gasotransmitters, namely carbon monoxide (CO), nitric oxide (NO) and hydrogen sulfide (H2S), have emerged as key modulators of tumor biology. These small, diffusible molecules exert a context-dependent spectrum of both pro-and anti-tumorigenic effects, influenced by their concentration, cellular source and tumor-specific microenvironmental conditions. Through the modulation of redox balance, metabolic signaling and epigenetic regulators, gasotransmitters impact immune cell functions, stromal remodeling and tumor cell behavior, thereby contributing to either immune evasion and therapy resistance or, conversely, to tumor suppression. Despite their growing relevance, the molecular mechanism governing these dualistic roles remain incompletely elucidated. This review provides a comprehensive overview of the current knowledge regarding the roles of CO, NO and H ₂ S in shaping TME. We focus on their influence on immune, stromal and tumor cell differentiation, metabolism and function, and discuss how this understanding could inform novel therapeutic strategies aimed at reprogramming the TME to enhance clinical outcomes in cancer treatment.