The active hormonal form of vitamin D, 1,25(OH)2D, regulates many components of the immune system and previous research shows that 1,25(OH)2D reduces the number and suppressive activity of MDSCs in tumors. This study aimed to evaluate the effects of calcitriol treatment on MDSCs in aged mice. We showed that aged BALB/c and CD1 mice exhibited increased levels of CD11b+Gr1+ cells in both the spleen and bone marrow compared to young mice. These cells displayed a less mature phenotype marked by reduced F4/80 expression and demonstrated robust T cell suppressive activity, as evidenced by their ability to inhibit the production of IFNγ and TNFα. Treatment of aged mice with calcitriol, administered twice weekly at a dose equivalent to 1 µg/kg for 4 weeks, significantly increased the population of CD11b+Gr1+ cells in the spleen, but not in the bone marrow of the animals, and promoted their differentiation into a more mature phenotype characterized by elevated F4/80 expression. In addition, calcitriol-treated aged mice exhibited significantly improved T cell responses, as indicated by increased IFNγ production upon specific antigen stimulation compared to the control group of mice. In vitro, calcitriol treatment of bone marrow-derived MDSCs similarly enhanced F4/80 expression without altering other markers such as CD11b, CD11c, or MHCII, and led to reduced expression of reactive oxygen species by these cells. Our study highlights the consistency of MDSC expansion across inbred and outbred mouse strains and supports the immunomodulatory role of calcitriol in promoting MDSC maturation and alleviating immune suppression in aging.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by its lack of estrogen, progesterone, and HER2 receptors, leading to limited treatment options and poor prognosis. This review synthesizes current research on the tumor microenvironment (TME) and immune cell crosstalk in TNBC to identify emerging therapeutic opportunities. The TME in TNBC is a complex ecosystem comprising immune cells, fibroblasts, and extracellular matrix components, which significantly influence tumor growth and metastasis. Single-cell RNA sequencing reveals T-cell heterogeneity and identifies prognostic genes. Regulatory T cells (Tregs) play a key role in immunosuppression, with thymidine kinase-1 (TK1) identified as a potential therapeutic target. MUC1-C and CXCL9 modulate the TME, impacting T-cell depletion and macrophage differentiation. Spatial analysis highlights the importance of cell-to-cell interactions in predicting recurrence. Epithelial-mesenchymal transition (EMT) and thermogenesis also influence the TME, while epigenetic modifications, such as HDAC inhibition, can induce pyroptosis and enhance immune cell recruitment. Integrating genomic information with TME analysis is crucial for developing personalized treatments, considering racial disparities in immune infiltration. Emerging therapies targeting immune checkpoints, modulating Treg activity, and inducing pyroptosis hold promise for improving TNBC patient outcomes. Future research should focus on multi-omics data, spatial transcriptomics, and patient-derived models to refine therapeutic interventions.

Inflammation is a complex and finely tuned component of the host defense mechanism, responding sensitively to a range of physical, chemical, and biological stressors. Current research is advancing our grasp of both cellular and molecular mechanisms that initiate and regulate interactions within inflammatory pathways. Substantial evidence now indicates a profound link between inflammation, innate immunity, and cancer. Dysregulation of inflammatory pathways is known to be a pivotal factor in the induction, growth, and metastasis of tumors through multiple mechanistic pathways. Basically, the tumor microenvironment (TME), characterized by dynamic interplay between cancerous cells and surrounding inflammatory and stromal cells, plays a central role in these processes. Increasingly, controlled acute inflammation is being explored as a promising therapeutic tool in certain types of cancer. However, inflammatory cells in the TME exhibit remarkable plasticity, with shifting phenotypic and functional roles that facilitate cancer cell survival, proliferation, and migration, especially under chronic inflammatory conditions. Additionally, signaling molecules associated with the innate immune system, like chemokines, are co-opted by malignant cells to support invasion, migration, and metastasis. These findings underscore the need for deeper insights into the mechanisms connecting inflammation to cancer pathology, which could pave the way for innovative diagnostic approaches and targeted anti-inflammatory therapies to counter tumor development. The current review underlines the critical involvement of inflammation in cancer development, examining the connection between the immune system, key inflammatory mediators, biomarkers, and their associated pathways in cancer. We also discuss the impact of inflammation-targeted therapies on anticancer signaling pathways. Furthermore, we review major anti-inflammatory drugs with potential applications in oncology, assessing how inflammation is modulated in cancer management. Lastly, we outline an overview of ongoing discoveries in the field, highlighting both the challenges and the therapeutic promise of targeting inflammation in cancer therapy.

The tumor microenvironment (TME) plays a crucial role in cancer development and spreading being considered as "the dark side of the tumor". Within this term tumor cells, immune components, supporting cells, extracellular matrix and a myriad of bioactive molecules that synergistically promote tumor development and therapeutic resistance, are included. Recent findings revealed the profound impacts of TME on cancer development, serving as physical support, critical mediator and biodynamic matrix in cancer evolution, immune modulation, and treatment outcomes. TME targeting strategies built on vasculature, immune checkpoints, and immuno-cell therapies, have paved the way for revolutionary clinical interventions. On this basis, the relevance of pre-clinical and clinical investigations has rapidly become fundamental for implementing novel therapeutical strategies breaking cell-cell and cell -mediators' interactions between TME components and tumor cells. This review summarizes the key players in the breast and pancreatic TME, elucidating the intricate interactions among cancer cells and their essential role for cancer progression and therapeutic resistance. Different tumors such breast and pancreatic cancer have both different and similar stroma features, that might affect therapeutic strategies. Therefore, this review aims to comprehensively evaluate recent findings for refining breast and pancreatic cancer therapies and improve patient prognoses by exploiting the TME's complexity in the next future.

Metastasis is the leading cause of cancer-related deaths. During the metastatic cascade, cancer cells tightly interact with immune cells influencing each other in the tumor microenvironment and systemically. Monocytes are important components of immune evasion and critical regulators of cancer progression. They circulate through the bloodstream and contribute to the formation of a pro-tumor microenvironment both in the tumor and pre-metastatic niche. Whereas monocyte participation in cancer development and response to therapy has been described extensively, its impact on metastasis remains a completely uncovered area. This review first summarizes data concerning the influence of monocytes on metastasis formation during their presence in the circulation, primary tumor, and pre-metastatic niche. We also highlight the latest examinations into the clinical relevance of targeting monocytes to prevent metastasis.

Tumor occurrence and growth are highly correlated with the degree of inflammation and immunological activity. Reducing the level of inflammation in tumor-bearing body to relieve immune suppression and enhance anti-tumor immune function has become an important strategy for tumor treatment.

To investigate the effect of albumin-bound paclitaxel combined with Sophora subprostrate polysaccharide (SSP) on inhibiting inflammation, reducing immunosuppression, enhancing anti-tumor immune function and slowing the progression of tumor in tumor-bearing rats, and to provide certain scientific basis for the clinical application of combined drugs in tumor.

The rats were put into three groups at random: normal control, model group, and drug treatment group. After the end of drug intervention, the tumor was taken out and weighed to observe the tumor growth of the rats. Tumor necrosis factor (TNF-α), interleukin (IL) 1β, IL-10, perforin, and granzyme B were found by Western blot in the local tumor tissues of experimental rats. The protein expression levels of Arginase-1 (Arg-1) and Cyclooxygenase 2 (COX-2) were determined. HE staining was used to observe the inflammatory infiltration of the tumor. Using flow cytometry, the proportions of anti-tumor immune cells-CD8 + T cells, NK cells, and immunosuppressive cells-in local tumor tissues were evaluated. In addition, spleen T cells isolated from normal rats were co-cultured with spleen myeloid derived suppressor cells (MDSC) from tumor-bearing rats in the model group and the combined treatment group. Cell Trace Far Red was used to identify T cell proliferation, flow cytometry was used to determine the level of T cell activation from CD25 expression, and in vivo immunosuppression in tumor-bearing rats was examined.

The combined therapy group experienced a considerable decrease in tumor weight as compared to the model group. TNF-α and IL-1p levels in the vicinity of the tumor tissues reduced following intervention, although IL-10 levels, which are anti-inflammatory cytokines, did not significantly change. The results of the HE staining revealed that the intervention group's tumor had less inflammatory infiltration than the model group did. After intervention, the percentages of CD8 + T cells and NK cells in local tumor tissues increased. Additionally, the intervention group's levels of protein expression for perforin and granzyme B were considerably higher than those of the model group. In the nearby tumor tissues, there were lots of MDSC. Following the intervention, the proportion of MDSC in the local tumor tissues was significantly reduced, and the expansion of MDSC was reduced. Additionally, the intervention group's COX-2 and Arg-1 protein expression levels in the tumor-specific tissues were significantly lower than those of the model group. The outcomes of in vitro co-culture demonstrated that rats in the combination group had higher levels of T cell proliferation and activation than animals in the model group.

Albumin-bound paclitaxel combined with Sophora subprostrate polysaccharide can reduce the local inflammation level, promote the proportion of CDB + T cells and NK cells and cell killing function, reduce the proportion of MDSC and immunosuppressive level, enhance the anti-tumor immune function of tumor-bearing mice, and slow the growth of tumors.

The aim of this study was to investigate the relationship between tumor microenvironment markers (myeloid-derived suppressor cells [MDSCs], regulatory T cells [Tregs], programmed cell death 1 [PD-1], and programmed death ligand 1 [PD-L1]) and chemotherapy efficacy and prognosis in advanced gastric cancer, identifying potential monitoring indicators.

Advanced gastric cancer patients' MDSC and Treg expression was measured by flow cytometry pre- and postchemotherapy; PD-1 and PD-L1 expression in cancer tissues was assessed by immunohistochemistry. Correlations with chemotherapy outcomes and prognosis were analyzed.

Postchemotherapy reductions in MDSC and Treg levels correlated with chemotherapy efficacy (P <.01). Negative PD-1 and PD-L1 expression in cancer tissues predicted better chemotherapy responses (P <.01). Patients with lower MDSC and Treg levels and negative PD-1 and PD-L1 had significantly longer median progression-free survival (PFS) and overall survival (OS) (P <.05).

In advanced gastric cancer, reduced peripheral blood MDSC and Treg levels postchemotherapy and negative PD-1 and PD-L1 expression in tissues are associated with improved chemotherapy efficacy and are independent prognostic factors for PFS and OS.

Integrin Mac-1 plays a critical role in the development of multiple sclerosis (MS); however, the underlying mechanism is not fully understood. Here, we developed a myeloid-specific Mac-1-deficient mouse. Using an experimental autoimmune encephalomyelitis (EAE) mouse model of MS, we report that Mac-1 on myeloid cells is key to disease development. Our data reveal that myeloid-specific Mac-1 significantly increases EAE severity and hinders disease regression. Loss of Mac-1 increases Gr-1+ cells in peripheral tissues and the CNS and preferably accelerates the transition of Ly6Chi monocytes from a pro-inflammatory to an immunosuppressive phenotype in a disease stage-dependent manner. Mechanistically, our results demonstrate that Mac-1 suppresses interferon-γ production and prevents monocytes from acquiring immunosuppressive functions by reducing the expression of iNOS, IDO, and CD84. Administration of a NOS-specific inhibitor in Mac-1-deficient EAE mice abolishes disease regression. These insights could help develop Mac-1-targeting strategies for better treatment of MS.

Long non-coding RNAs (lncRNAs) have emerged as critical regulators in cancer biology, particularly in the modulation of innate immune cells within the tumor microenvironment. These lncRNAs significantly influence the phenotype and function of immune cells, such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), natural killer cells (NK), neutrophils, and γδT cells. Thus, lncRNAs emerge as pivotal molecules in cancer development due to their capacity to modulate the innate immune system. Understanding the intricate mechanisms by which lncRNAs influence tumor-associated immune cells can pave the way for novel therapeutic strategies to restore effective anti-tumor immunity. This review highlights the diverse roles of lncRNAs in regulating the differentiation, activation, and effector functions of innate immune cells within the complex tumor microenvironment.

How tumor microenvironment shapes lung adenocarcinoma (LUAD) precancer evolution remains poorly understood. Spatial immune profiling of 114 human LUAD and LUAD precursors reveals a progressive increase of adaptive response and a relative decrease of innate immune response as LUAD precursors progress. The immune evasion features align the immune response patterns at various stages. TIM-3-high features are enriched in LUAD precancers, which decrease in later stages. Furthermore, single-cell RNA sequencing (scRNA-seq) and spatial immune and transcriptomics profiling of LUAD and LUAD precursor specimens from 5 mouse models validate high TIM-3 features in LUAD precancers. In vivo TIM-3 blockade at precancer stage, but not at advanced cancer stage, decreases tumor burden. Anti-TIM-3 treatment is associated with enhanced antigen presentation, T cell activation, and increased M1/M2 macrophage ratio. These results highlight the coordination of innate and adaptive immune response/evasion during LUAD precancer evolution and suggest TIM-3 as a potential target for LUAD precancer interception.

T cell engagers (TCEs) represent a groundbreaking advancement in the treatment of B and plasma cell malignancies and are emerging as a promising therapeutic approach for the treatment of solid tumors. These molecules harness T cells to bind to and eliminate cancer cells, effectively bypassing the need for antigen-specific T cell recognition. Despite their established clinical efficacy, a subset of patients is either refractory to TCE treatment (e.g. primary resistance) or develops resistance during the course of TCE therapy (e.g. acquired or treatment-induced resistance). In this review we comprehensively describe the resistance mechanisms to TCEs, occurring in both preclinical models and clinical trials with a particular emphasis on cellular and molecular pathways underlying the resistance process. We classify these mechanisms into tumor intrinsic and tumor extrinsic ones. Tumor intrinsic mechanisms encompass changes within tumor cells that impact the T cell-mediated cytotoxicity, including tumor antigen loss, the expression of immune checkpoint inhibitory ligands and intracellular pathways that render tumor cells resistant to killing. Tumor extrinsic mechanisms involve factors external to tumor cells, including the presence of an immunosuppressive tumor microenvironment (TME) and reduced T cell functionality. We further propose actionable strategies to overcome resistance offering potential avenues for enhancing TCE efficacy in the clinic.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by a progressive breakdown of immune tolerance to self-antigens, resulting in multiple tissue damage and clinical symptoms. Innate and adaptive immune cells including dendritic cells, macrophages, myeloid-derived suppressor cells (MDSCs), T cells and B cells are the key drivers in perpetuating and amplifying of this systemic disease. In this review we offer a comprehensive overview of recent advances in understanding the immune-pathogenesis of SLE with particular emphasis on regulatory immune cells exhibiting immunosuppressive properties, as well as newly identified factors influencing immune cell function and lineage differentiation. Furthermore, we discuss traditional Chinese medicine and natural extracts that have shown therapeutic effects on SLE by modulating immune cell differentiation and function, which may provide insights into their clinical applications.

Myeloid-derived suppressor cells (MDSCs) are expanded in cancer patients, have an intrinsic immunosuppressive function, and thus may play a role in resistance to immunotherapy. Ulceration of the melanoma primary is associated with more aggressive disease and is an independent prognostic factor for melanoma-specific survival. However, the underlying factors contributing to this more aggressive phenotype are not completely understood. The current study aims to correlate changes in circulating MDSC during immunotherapy in patients with ulcerated vs non-ulcerated melanoma primary tumors. Longitudinal changes in levels of circulating MDSCs were analyzed via flow cytometry in melanoma patients receiving immune checkpoint inhibitors (ICIs) and stratified by ulceration status. Following the initiation of therapy, the percentage of total MDSCs increased significantly in patients with both ulcerated ( P  = 0.003) and non-ulcerated ( P  < 0.001) tumors. When MDSCs were stratified by subset, the proportion of granulocytic MDSC (PMN-MDSC) decreased in patients with non-ulcerated tumors ( P  = 0.023), while the proportion remained stable in patients with ulcerated tumors ( P  = 0.121). The reduction in the proportion PMN-MDSC in non-ulcerated patients coincided with a statistically significant increase in the proportion of CD14 + /CD15 + MDSC ( P  = 0.008), resulting in a greater proportion of CD14 + /CD15 + MDSC in non-ulcerated patients as compared to ulcerated melanoma patients following two infusions of ICIs (27.3 ± 19.2% vs 16.1 ± 19.2%; P  = 0.008). The trajectories of the MDSC populations described here provide insight into the altered tumor microenvironment in ulcerated melanoma and highlight key changes in a cell population that could contribute to immunotherapy resistance.

Myeloid-derived suppressor cells (MDSCs) are believed to be key promoters of tumor development and are recognized as a hallmark of cancer cells' ability to evade the immune system evasion. MDSC levels often increase in peripheral blood and the tumor microenvironment (TME). These cells exert immunosuppressive functions, weakening the anticancer immune surveillance system, in part by repressing T-cell immunity. Moreover, MDSCs may promote tumor progression and interact with cancer cells, increasing MDSC expansion and favoring an immunotolerant TME. This review analyzes the primary roles of MDSCs in cancer and T-cell immunity, discusses the urgent need to develop effective MDSC-targeted therapies, and highlights the potential synergistic combination of MDSC targeting with chimeric antigen receptors and immune checkpoint inhibitors.

Cancer-associated myeloid cells due to their plasticity play dual roles in both promoting and inhibiting tumor progression. Myeloid cells with immunosuppressive properties play a critical role in anti-cancer immune regulation. Cells of different origin, such as tumor associated macrophages (TAMs), tumor associated neutrophils (TANs), myeloid derived suppressor cells (also called MDSCs) and eosinophils are often expanded in cancer patients and significantly influence their survival, but also the outcome of anti-cancer therapies. For this reason, the variety of preclinical and clinical studies to modulate the activity of these cells have been conducted, however without successful outcome to date. In this review, pro-tumor activity of myeloid cells, myeloid cell-specific therapeutic targets, in vivo studies on myeloid cell re-polarization and the impact of myeloid cells on immunotherapies/genetic engineering are addressed. This paper also summarizes ongoing clinical trials and the concept of chimeric antigen receptor macrophage (CAR-M) therapies, and suggests future research perspectives, offering new opportunities in the development of novel clinical treatment strategies.

Klebsiella pneumoniae (Kp) is responsible for a wide range of infections, including pneumonia, sepsis, and urinary tract infections. However, the treatment options are limited due to the continuous evolution of drug-resistant and hypervirulent variants. It is crucial to investigate the mechanisms behind the high mortality rate of hypervirulent Kp (hvKp) strains to develop new strategies for preventing hvKp from evading the host's defenses and improving treatment effectiveness for these fatal infections. In this study, we used a hvKp-induced mouse bacteremia model and performed single-cell RNA sequencing to investigate the effects of hvKp infection. Our findings demonstrated that hvKp infection led to a decrease in lymphocytes (lymphopenia), attributed to impaired proliferation and apoptosis. The infiltration of myeloid-derived suppressor cells (MDSCs) in the infected lungs was confirmed to suppress T cell proliferation, leading to lymphopenia. We further identified that hvKp promotes tryptophan metabolism in infected lungs, enhancing the immunosuppressive activity of MDSCs by inducing the production of the enzyme IDO1. Our ex vivo inhibition experiment revealed that L-kynurenine, a product of tryptophan metabolism, inhibits T-cell proliferation and induces T-cell apoptosis, further suppressing T-cell mediated responses against bacteria. Importantly, when we knocked out the Ido1 gene or inhibited IDO1 expression using a specific inhibitor 1-MT in mice, we observed a significant enhancement in T-cell mediated responses against hvKp. These findings highlight the crucial role of MDSCs in hvKp-induced bacteremia and suggest a promising immunotherapeutic approach by inhibiting IDO1 production to combat infectious diseases.

Iron metabolism plays a crucial role in the tumor microenvironment, influencing various aspects of cancer cell biology and tumor progression. This review discusses the regulatory mechanisms of iron metabolism within the tumor microenvironment and highlights how tumor cells and associated stromal cells manage iron uptake, accumulation and regulation. The sources of iron within tumors and the biological importance of ferroptosis in cancer were explored, focusing on its mechanisms, biological effects and, in particular, its tumor‑suppressive properties. Furthermore, the protective strategies employed by cancer cells to evade ferroptosis were examined. This review also delves into the intricate relationship between iron metabolism and immune modulation within the tumor microenvironment, detailing the impact on tumor‑associated immune cells and immune evasion. The interplay between ferroptosis and immunotherapy is discussed and potential strategies to enhance cancer immunotherapy by modulating iron metabolism are presented. Finally, the current ferroptosis‑based cancer therapeutic approaches were summarized and future directions for therapies that target iron metabolism were proposed.

Metastatic disease is the leading cause of cancer-related death, despite recent advances in therapeutic interventions. Prior modeling approaches have accounted for the adaptive immune system's role in combating tumors, which has led to the development of stochastic models that explain cancer immunoediting and tumor-immune co-evolution. However, cancer immune-mediated dormancy, wherein the adaptive immune system maintains a micrometastatic population by keeping its growth in check, remains poorly understood. Immune-mediated dormancy can significantly delay the emergence (and therefore detection) of metastasis. An improved quantitative understanding of this process will thereby improve our ability to identify and treat cancer during the micrometastatic period. Here, we introduce a generalized stochastic model that incorporates the dynamic effects of immunomodulation within the tumor microenvironment on T cell-mediated cancer killing. This broad class of nonlinear birth-death model can account for a variety of cytotoxic T cell immunosuppressive effects, including regulatory T cells, cancer-associated fibroblasts, and myeloid-derived suppressor cells. We develop analytic expressions for the likelihood and mean time of immune escape. We also develop a method for identifying a corresponding diffusion approximation applicable to estimating population dynamics across a wide range of nonlinear birth-death processes. Lastly, we apply our model to estimate the nature and extent of immunomodulation that best explains the timing of disease recurrence in bladder and breast cancer patients. Our findings quantify the effects that stochastic tumor-immune interaction dynamics can play in the timing and likelihood of disease progression. Our analytical approximations provide a method of studying population escape in other ecological contexts involving nonlinear transition rates.

Metabolic reprogramming is one of the major biological features of malignant tumors, playing a crucial role in the initiation and progression of cancer. The tumor microenvironment consists of various non-cancer cells, such as hepatic stellate cells, cancer-associated fibroblasts (CAFs), immune cells, as well as extracellular matrix and soluble substances. In liver cancer, metabolic reprogramming not only affects its own growth and survival but also interacts with other non-cancer cells by influencing the expression and release of metabolites and cytokines (such as lactate, PGE2, arginine). This interaction leads to acidification of the microenvironment and restricts the uptake of nutrients by other non-cancer cells, resulting in metabolic competition and symbiosis. At the same time, metabolic reprogramming in neighboring cells during proliferation and differentiation processes also impacts tumor immunity. This article provides a comprehensive overview of the metabolic crosstalk between liver cancer cells and their tumor microenvironment, deepening our understanding of relevant findings and pathways. This contributes to further understanding the regulation of cancer development and immune evasion mechanisms while providing assistance in advancing personalized therapies targeting metabolic pathways for anti-cancer treatment.

Breast cancer (BC) ranks among the most prevalent malignancies affecting women, with advanced-stage patients facing an increased mortality risk. Myeloid-derived suppressor cells (MDSCs) contribute significantly to poor prognostic outcomes. Research has concentrated predominantly on the immunological mechanisms underlying MDSC functions, but a comprehensive investigation into the metabolic interactions between BC cells and MDSCs is lacking. In a hypoxic tumor microenvironment (TME), BC cells can enhance aerobic-glycolysis rates, upregulate expression of key lipid metabolism enzymes such as cluster of differentiation (CD) 36 and 5-lipoxygenase (5-LOX), accelerate glutamine (Gln) uptake, and elevate extracellular adenosine (eADO) levels, thereby fostering MDSC proliferation and amplifying immune suppression. Concurrently, alterations in the metabolic state of MDSCs also influence BC progression. To ensure adequate proliferative resources, MDSCs upregulate the pentose phosphate pathway and expedite glycolysis for energy supply while increasing the expression of fatty acid transport proteins (FATPs) such as CD36 and fatty acid transporter 2 (FATP2) to maintain intracellular lipid availability, thereby enhancing their adaptability within the TME. Furthermore, MDSCs undermine T-cell anti-tumor efficacy by depleting essential amino acids (AAs), such as arginine (Arg), tryptophan (Trp), and cysteine (Cys), required for T-cell function. This review elucidates how pharmacological agents such as metformin, liver X receptor (LXR) agonists, and 6-diazo-5-oxo-L-norleucine (DON) can augment anti-cancer treatment efficacy by targeting metabolic pathways in MDSCs. We systematically delineate the mechanisms governing interactions between BC cells and MDSCs from a metabolic standpoint while summarizing therapeutic strategies to modulate metabolism within MDSCs. Our review provides a framework for optimizing MDSC applications in BC immunotherapy.

Amino acids are pivotal regulators of immune cell metabolism, signaling pathways, and gene expression. In myeloid cells, these processes underlie their functional plasticity, enabling shifts between pro-inflammatory, anti-inflammatory, pro-tumor, and anti-tumor activities. Within the tumor microenvironment, amino acid metabolism plays a crucial role in mediating the immunosuppressive functions of myeloid cells, contributing to tumor progression. This review delves into the mechanisms by which specific amino acids-glutamine, serine, arginine, and tryptophan-regulate myeloid cell function and polarization. Furthermore, we explore the therapeutic potential of targeting amino acid metabolism to enhance anti-tumor immunity, offering insights into novel strategies for cancer treatment.

MDSCs are immature neutrophils and monocytes with immunosuppressive potentials, involving mononuclear MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs).

They are significant components of the tumor microenvironment (TME). Besides, recent studies also verified that MDSCs also facilitated the progression of bone metastasis by regulating the network of cytokines and the function of immune cells.

It is necessary to summarize the mechanisms of MDSC recruitment and immunosuppression, and their impact on bone metastasis.

Ferroptosis, an iron-dependent form of regulated cell death, is driven by lipid peroxidation and shaped by metabolic and antioxidant pathways. In immune cells, ferroptosis susceptibility varies by cell types, lipid composition, and metabolic demands, influencing immune responses in cancer, infections, and autoimmune diseases. Therapeutically, targeting ferroptosis holds promise in cancer immunotherapy by enhancing antitumor immunity or inhibiting immunosuppressive cells. This review highlights the metabolic pathways underlying ferroptosis, its regulation in immune cells, its dual role in tumor progression and antitumor immunity, and its context-dependent therapeutic implications for optimizing cancer treatment.

Myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME) contribute to the malignant progression of tumors by exerting immunosuppressive effects. Bacterial lipopolysaccharides (LPS) have been widely demonstrated in various types of solid tumors. LPS can promote the malignant progression of tumors, which mechanism has not yet been fully elucidated. In this study, a type of MDSC-like tumor cells (MLTCs) is found in tumor tissues induced by low-dose and long-term LPS stimulation. MLTCs can simultaneously express tumor cell and MDSCs markers. Similar to MDSCs, MLTCs can produce arginine, nitric oxide, and reactive oxygen species and inhibit the activity of NK and T cells to promote the formation of an immunosuppressive microenvironment. MLTCs can also promote tumor cell proliferation and vasculogenic mimicry formation. CRISPR-Cas9 activity screening studies identified RNA-binding Fox-1 homolog 3 (Rbfox3) as a critical protein for MLTCs formation after LPS treatment. Rbfox3 can transcriptionally regulate the expression of Ass1 in the form of phase-separated particles. Crocin can inhibit the generation of MLTCs by disrupting phase-separated particles of Rbfox3 and enhance the anti-tumor effects of immune checkpoint inhibitors (ICIs).

As a novel form of cell death, ferroptosis is mainly regulated by the accumulation of soluble iron ions in the cytoplasm and the production of lipid peroxides and is closely associated with several diseases, including acute kidney injury, ischemic reperfusion injury, neurodegenerative diseases, and cancer. The term "immunosuppression" refers to various factors that can directly harm immune cells' structure and function and affect the synthesis, release, and biological activity of immune molecules, leading to the insufficient response of the immune system to antigen production, failure to successfully resist the invasion of foreign pathogens, and even organ damage and metabolic disorders. An immunosuppressive phase commonly occurs in the progression of many ferroptosis-related diseases, and ferroptosis can directly inhibit immune cell function. However, the relationship between ferroptosis and immunosuppression has not yet been published due to their complicated interactions in various diseases. Therefore, this review deeply discusses the contribution of ferroptosis to immunosuppression in specific cases. In addition to offering new therapeutic targets for ferroptosis-related diseases, the findings will help clarify the issues on how ferroptosis contributes to immunosuppression.

Liver cancer is one of the most challenging malignancies, often associated with poor prognosis and limited treatment options. Recent advancements in nanotechnology and artificial intelligence (AI) have opened new frontiers in the fight against this disease. Nanotechnology enables precise, targeted drug delivery, enhancing the efficacy of therapeutics while minimizing off-target effects. Simultaneously, AI contributes to improved diagnostic accuracy, predictive modeling, and the development of personalized treatment strategies. This review explores the convergence of nanotechnology and AI in liver cancer treatment, evaluating current progress, identifying existing research gaps, and discussing future directions. We highlight how AI-powered algorithms can optimize nanocarrier design, facilitate real-time monitoring of treatment efficacy, and enhance clinical decision-making. By integrating AI with nanotechnology, clinicians can achieve more accurate patient stratification and treatment personalization, ultimately improving patient outcomes. This convergence holds significant promise for transforming liver cancer therapy into a more precise, individualized, and efficient process. However, data privacy, regulatory hurdles, and the need for large-scale clinical validation remain. Addressing these issues will be essential to fully realizing the potential of these technologies in oncology.

Cancer cells must reprogram their metabolism to sustain rapid growth. This is accomplished in part by switching to aerobic glycolysis, uncoupling glucose from mitochondrial metabolism, and performing anaplerosis via alternative carbon sources to replenish intermediates of the tricarboxylic acid (TCA) cycle and sustain oxidative phosphorylation (OXPHOS). While this metabolic program produces adequate biosynthetic intermediates, reducing agents, ATP, and epigenetic remodeling cofactors necessary to sustain growth, it also produces large amounts of byproducts that can generate a hostile tumor microenvironment (TME) characterized by low pH, redox stress, and poor oxygenation. In recent years, the focus of cancer metabolic research has shifted from the regulation and utilization of cancer cell-intrinsic pathways to studying how the metabolic landscape of the tumor affects the anti-tumor immune response. Recent discoveries point to the role that secreted metabolites within the TME play in crosstalk between tumor cell types to promote tumorigenesis and hinder the anti-tumor immune response. In this review, we will explore how crosstalk between metabolites of cancer cells, immune cells, and stromal cells drives tumorigenesis and what effects the competition for resources and metabolic crosstalk has on immune cell function.

The advent of immune checkpoint inhibition has revolutionized treatment of advanced melanoma. While most patients derive survival benefit from established immunotherapies, notably monoclonal antibodies blocking cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1, a subset does not optimally respond due to the manifestation of innate or acquired resistance to these therapies. Combination regimens have proven efficacious relative to single-agent blockade, but also yield high-grade treatment toxicities that are often dose-limiting for patients. In this review, we discuss the significant strides made in the past half-decade toward expanding the melanoma immunotherapy treatment paradigm. These include newly approved therapies, adoption of neoadjuvant immunotherapy, and studies in the clinical trials pipeline targeting alternative immune checkpoints and key immunoregulatory molecules. We then review how developments in molecular and functional diagnostics have furthered our understanding of the tumor-intrinsic and -extrinsic mechanisms driving immunotherapy resistance, as well as highlight novel biomarkers for predicting treatment response. Throughout, we discuss potential approaches for targeting these resistance mechanisms in rational combination with established immunotherapies to improve outcomes for patients with melanoma.

Cancer treatment has witnessed revolutionary advancements marked by the emergence of immunotherapy, specifically immune checkpoint blockade (ICB). However, the inherent low immunogenicity of tumor cells and the intricate immunosuppressive network within the tumor microenvironment (TME) pose significant challenges to the further development of immunotherapy. Nanotechnology has ushered in unprecedented opportunities and vast prospects for tumor immunotherapy. Nevertheless, traditional nano-formulations often rely on inducing apoptosis to kill cancer cells, which encounters the issue of immune silencing, hindering effective tumor immune activation. The non-apoptotic modes of regulated cell death (RCD), including pyroptosis, ferroptosis, autophagy, necroptosis, and cuproptosis, have gradually garnered attention. These non-apoptotic cell death pathways can induce effective immunogenic cell death (ICD), enhancing cancer immunotherapy. This review comprehensively explores advanced nano-formulation design strategies and their applications in enhancing cancer immunotherapy by promoting non-apoptotic RCD in recent years. It also discusses the potential advantages of these strategies in inducing tumor-specific non-apoptotic RCD. By deeply understanding the significance of non-apoptotic RCD in synergistic cancer immunotherapy, this article provides valuable insights for developing more advanced nano-delivery systems that can robustly induce highly immunogenic non-apoptotic modes, offering novel research and development avenues to address the clinical challenges encountered by immunotherapy represented by ICB.

Chimeric antigen receptor (CAR) T cell therapies have transformed outcomes for many patients with hematological malignancies. However, some patients do not respond to CAR T cell treatment, and adapting CAR T cells for treatment of solid and brain tumors has been met with many challenges, including a hostile tumor microenvironment and poor CAR T cell persistence. Thus, it is unlikely that CAR T cell therapy alone will be sufficient for consistent, complete tumor clearance across patients with cancer. Combinatorial therapies of CAR T cells and chemotherapeutics are a promising approach for overcoming this because chemotherapeutics could augment CAR T cells for improved antitumor activity or work in tandem with CAR T cells to clear tumors. Herein, we review efforts toward achieving successful CAR T cell and chemical drug combination therapies. We focus on combination therapies with approved chemotherapeutics because these will be more easily translated to the clinic but also review nonapproved chemotherapeutics and drug screens designed to reveal promising new CAR T cell and chemical drug combinations. Overall, this review highlights the promise of CAR T cell and chemotherapy combinations with a specific focus on how combinatorial therapy overcomes challenges faced by either monotherapy and supports the potential of this therapeutic strategy to improve outcomes for patients with cancer. SIGNIFICANCE STATEMENT: Improving currently available CAR T cell products via combinatorial therapy with chemotherapeutics has the potential to drastically expand the types of cancers and number of patients that could benefit from these therapies when neither alone has been sufficient to achieve tumor clearance. Herein, we provide a thorough review of the current efforts toward studying CAR T and chemotherapy combinatorial therapies and offer perspectives on optimal ways to identify new and effective combinations moving forward.

Biliary tract cancers (BTC) are a highly heterogeneous group of cancers at the genomic, epigenetic and molecular levels. The vast majority of patients initially present at an advanced (unresectable) disease stage due to a lack of symptoms and an aggressive tumour biology. Chemotherapy has been the mainstay of treatment in patients with advanced BTC but the survival outcomes and prognosis remain poor. The addition of immune checkpoint inhibitors (ICI) to chemotherapy have shown only a marginal benefit over chemotherapy alone due to the complex tumour immune microenvironment of these cancers. This review appraises our current understanding of the immune landscape of advanced BTC, including emerging transcriptome-based classifications, highlighting the mechanisms of immune evasion and resistance to ICI and their therapeutic implications. It describes the shifting treatment paradigm from traditional chemotherapy to immunotherapy combinations as well as the potential biomarkers for predicting response to ICI.

Amino acid metabolism in breast cancer cells is unique for each molecular biological subtype of breast cancer. In this review, the features of breast cancer cell metabolism are considered in terms of changes in the amino acid composition due to the activity of transmembrane amino acid transporters. In addition to the main signaling pathway PI3K/Akt/mTOR, the activity of the oncogene c-Myc, HIF, p53, GATA2, NF-kB and MAT2A have a direct effect on the amino acid metabolism of cancer cells, their growth and proliferation, as well as the maintenance of homeostatic equilibrium. A distinctive feature of luminal subtypes of breast cancer from TNBC is the ability to perform gluconeogenesis. Breast cancers with a positive expression of the HER2 receptor, in contrast to TNBC and luminal A subtype, have a distinctive active synthesis and consumption of fatty acids. It is interesting to note that amino acid transporters exhibit their activity depending on the pH level inside the cell. In the most aggressive forms of breast cancer or with the gradual progression of the disease, pH will also change, which will directly affect the metabolism of amino acids. Using the cell lines presented in this review, we can trace the characteristic features inherent in each of the molecular biological subtypes of breast cancer and develop the most optimal therapeutic targets.

Preventive vaccination is a crucial strategy for controlling and preventing infectious diseases, offering both effectiveness and cost-efficiency. However, despite the widespread success of vaccination programs, there are still certain population groups who struggle to mount adequate responses to immunization. These at-risk groups include but are not restricted to the elderly, overweight individuals, individuals with chronic infections and cancer patients. All of these groups are characterized by persistent chronic inflammation. Recent studies have demonstrated that one of the key players in immune regulation and the promotion of chronic inflammation are myeloid-derived suppressor cells (MDSCs). These cells possess a wide range of immunosuppressive mechanisms and are able to dampen immune responses in both antigen-specific and antigen-nonspecific manner, thus contributing to the establishment and maintenance of an inflammatory environment. Given their pivotal role in immune modulation, there is growing interest in understanding how MDSCs may influence the efficacy of vaccines, particularly in vulnerable populations. In this narrative review, we discuss whether MDSCs are able to regulate vaccine-induced immunity and whether their suppression can potentially enhance vaccine efficacy in vulnerable populations.

Chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable success in hematologic malignancies but has encountered challenges in effectively treating solid tumors. One major obstacle is the presence of the immunosuppressive tumor microenvironment (TME), which is mainly built by myeloid-derived suppressor cells (MDSCs). Recent studies have shown that MDSCs have a detrimental effect on CAR-T cells due to their potent immunosuppressive capabilities. Targeting MDSCs has shown promising results to enhance CAR-T immunotherapy in preclinical solid tumor models. In this review, we first highlight that MDSCs increase tumor proliferation, transition, angiogenesis and encourage circulating tumor cells (CTCs) extravasation leading to tumor progression and metastasis. Moreover, we describe the main characteristics of the immunosuppressive activities of MDSCs on T cells in TME. Most importantly, we summarize targeting therapeutic strategies of MDSCs in CAR-T therapies against solid tumors. These strategies include (1) therapeutic targeting of MDSCs through small molecule inhibitors and large molecule antibodies; (2) CAR-T targeting cancer cell antigen combination with MDSC modulatory agents; (3) cytokine receptor antigen-targeted CAR-T indirectly or directly targeting MDSCs reshapes TME; (4) modified natural killer (NK) cells expressing activating receptor directly targeting MDSCs; and (5) CAR-T directly targeting MDSC selective antigens. In the near future, we are expected to witness the improvement of CAR-T cell therapies for solid tumors by targeting MDSCs in clinical practice.

Ferroptosis is a non-apoptotic form of regulated cell death characterized by iron accumulation and uncontrolled lipid peroxidation, leading to plasma membrane rupture and intracellular content release. Cancer immunotherapy, especially immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1, has been considered a breakthrough in cancer treatment, achieving encouraging clinical anti-tumor effects in a variety of cancers. However, tumor immune evasion is indispensable to immunotherapy failure. The mechanisms of tumor immune evasion are quite complex, and its occurrence is inseparable from the ferroptosis in tumor microenvironment (TME). Thus, a comprehensive understanding of the role of ferroptosis in tumor immune evasion is crucial to enhance the efficacy of immunotherapy. In this review, we provide an overview of the recent advancements in understanding ferroptosis in cancer, covering molecular mechanisms and interactions with the TME. We also summarize the potential applications of ferroptosis induction in immunotherapy, as well as ferroptosis inhibition for cancer treatment in various conditions. We finally discuss ferroptosis as a double-edged sword, including the current challenges and future directions regarding its potential for cancer treatment.

Small cell lung cancer (SCLC) is aggressive with limited therapeutic options. Despite recent advances in targeted therapies and immunotherapies, therapy resistance is a recurring issue, which might be partly due to tumor cell plasticity, a change in cell fate. Nonetheless, the mechanisms underlying tumor cell plasticity and immune evasion in SCLC remain elusive. CRACD, a capping protein inhibitor that promotes actin polymerization, is frequently inactivated in SCLC. Cracd knockout (KO) transforms preneoplastic cells into SCLC tumor-like cells and promotes in vivo SCLC development driven by Rb1, Trp53, and Rbl2 triple KO. Cracd KO induces neuroendocrine (NE) plasticity and increases tumor cell heterogeneity of SCLC tumor cells via dysregulated NOTCH1 signaling by actin cytoskeleton disruption. CRACD depletion also reduces nuclear actin and induces EZH2-mediated H3K27 methylation. This nuclear event suppresses the MHC-I genes and thereby depletes intratumoral CD8+ T cells for accelerated SCLC tumorigenesis. Pharmacological blockade of EZH2 inhibits CRACD-negative SCLC tumorigenesis by restoring MHC-I expression and immune surveillance. Unsupervised single-cell transcriptomics identifies SCLC patient tumors with concomitant inactivation of CRACD and downregulated MHC-I pathway. This study defines CRACD, an actin regulator, as a tumor suppressor that limits cell plasticity and immune evasion and proposes EZH2 blockade as a viable therapeutic option for CRACD-negative SCLC.

Immune checkpoint inhibitors (ICIs) have profoundly reshaped the treatment paradigm for non-small cell lung cancer (NSCLC). Despite these advancements, primary and secondary resistance to ICIs remain prevalent challenges in managing advanced NSCLC. Recent studies have highlighted the significant role of the tumor microenvironment (TME) in modulating treatment responses. This review aims to comprehensively examine the interactive roles of immune/stromal cells-such as T cells, B cells, neutrophils, macrophages, and CAFs within the TME, elucidating how these diverse cellular interactions contribute to immunotherapy resistance. It focuses on the dynamic interactions among diverse cell types such as the varying states of T cells under the influence of TME constituents like immune cells and cancer-associated fibroblasts (CAFs). By exploring the mechanisms involved in the complex cellular interactions, we highlight novel therapeutic targets and strategies aimed at overcoming resistance, thereby enhancing the efficacy of ICIs in NSCLC. Our synthesis of recent research provides critical insights into the multifaceted mechanisms of resistance and paves the way for the development of more effective, personalized treatment approaches.

Age-related changes initiate a cascade of cellular and molecular alterations that lead to immune system dysfunction or abnormal activation, predisposing individuals to age-related diseases. This phenomenon, commonly referred to as immunosenescence, highlighting aging-associated progressive decline of the immune system. Moreover, mounting evidence suggests that immunosenescence contributes to a related pathological phenomenon known as inflammaging. Inflammaging refers to chronic, low-grade, and systemic inflammation associated with aging, occurring despite the absence of overt stimuli. In the body, inflammation is typically activated in response to overt stimuli such as bacterial/microbial invasion or a pathological state, however, inflammaging occurrence and its underpinning mechanisms seem to be independent and in the absence of such stimuli. Despite recent advancements in molecular characterization and the scrutiny of disease relevance, these two interconnected concepts have remained largely unexplored and unrecognized. In this comprehensive review, we aim to shed light on the mechanistic and cellular aspects of immunosenescence and inflammaging, as well as their pivotal roles in the pathogenesis of aging-related diseases, including cancer, infections, dementia, and neurodegenerative disorders.