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Polymorphonuclear neutrophils (PMNs) are innate cells that may act as myeloid-derived suppressor cells (MDSCs), most often characterized by their immunosuppressive capacity towards immune cells within the tumor microenvironment. Over the last decade, many studies have tried to characterize these PMN-MDSCs. Although all human neutrophils obtain suppressive activity upon activation, specialized subsets, including low-density cells, have been proposed to exert MDSC activity without requiring prior stimulation. Single-cell RNA sequencing (scRNAseq) has created a new horizon to study possible neutrophil subsets. As such, the identification of distinct neutrophil subtypes in tumors may better characterize immunosuppressive neutrophils, in the end leading to specific targeting strategies in cancer patients. Nevertheless, scRNAseq has not yet led to a clear immunophenotypic characterization of PMN-MDSCs, and clinical relevance by functional testing is still lacking. Studies on the discrepancy in RNA abundance, protein expression and functionality in neutrophils indicate that the future for defining functional neutrophil subsets will rely on further development of single-cell techniques, like proteomics, to truly carve out neutrophil subsets and plasticity.

Neutrophils have been extensively described in the pathophysiology of autoimmune and infectious diseases. Accumulating evidence also suggests the important role of neutrophils in cancer progression through their interaction with cancer and immune cells in blood and in the tumor microenvironment (TME). Most studies have described neutrophils as key drivers of cancer progression, due to their involvement in various tumor promoting functions including proliferation, aggressiveness, and dissemination, as well as in immune suppression. However, such studies were focusing on late-stages of tumorigenesis, in which chronic inflammation had already developed. The role of tumor-associated neutrophils (TANs) at early stages of tumor development remains poorly described, though recent findings indicate that early-stage TANs may display anti-tumor properties. Beyond their role at tumor site, evidence supported by NLR retrospective studies and functional analyses suggest that blood neutrophils could also actively contribute to tumorigenesis. Hence, it appears that the phenotype and functions of neutrophils vary greatly during tumor progression, highlighting their heterogeneity. The origin of pro- or anti-tumor neutrophils is generally believed to arise following a change in cell state, from resting to activated. Moreover, the fate of neutrophils may also involve distinct differentiation programs yielding various subsets of pro or anti-tumor neutrophils. In this review, we will discuss the current knowledge on neutrophils heterogeneity across different tissues and their impact on tumorigenesis, as well as neutrophil-based therapeutic strategies that have shown promising results in pre-clinical studies, paving the way for the design of neutrophil-based next generation immunotherapy.

Background This study investigates the clinical significance of myeloid-derived suppressor cells (MDSCs), including polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs) subsets, and regulatory T cells (Tregs) in the peripheral blood of breast cancer patients. Methods Using flow cytometry, we analyzed levels of these immunosuppressive cell populations in 107 breast cancer patients and 33 healthy controls at the Breast Centre of the Fourth Hospital of Hebei Medical University (July-November 2021). Results Levels of MDSCs, PMN-MDSCs, M-MDSCs, and Tregs were significantly elevated in breast cancer patients compared to controls ( P  < 0.05). Furthermore, MDSCs, PMN-MDSCs, and Tregs showed a strong positive correlation with lymph node metastasis ( P  < 0.001). M-MDSCs were also significantly associated, though to a lesser extent ( P  = 0.045). Receiver operating characteristic (ROC) curve analysis revealed high diagnostic value for these cells in breast cancer. Notably, Tregs exhibited the highest individual area under the curve (AUC = 0.766) for detecting lymph node metastasis. Critically, the combined assessment of MDSCs and Tregs significantly enhanced predictive accuracy for lymph node metastasis, yielding a combined AUC exceeding that of any single marker. Conclusion Elevated levels of MDSCs (and their subsets) and Tregs are closely associated with lymph node metastasis in breast cancer. Their combined detection provides an effective predictive tool for lymph node involvement and holds substantial clinical value.

Myeloid-derived suppressor cells (MDSCs) play roles in immune regulation during neoplastic and non-neoplastic inflammatory responses. This immune regulatory function is directed mainly toward T cells. However, MDSCs also regulate other cell populations, including B cells, during inflammatory responses. Indeed, B cells are essential for antibody-mediated immune responses. MDSCs regulate B cell immune responses directly via expression of effector molecules and indirectly by controlling other immune regulatory cells. B cell-mediated immune responses are a major component of the overall immune response; thus, MDSCs play a prominent role in their regulation. Here, we review the current knowledge about MDSC-mediated regulation of B cell responses.

Myeloid‐derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that expand aberrantly in cancer and exhibit potent immunosuppressive properties. They contribute to tumor progression through both immunological and nonimmunological mechanisms. Immunologically, MDSCs suppress antitumor responses by inhibiting effector cells such as T cells and NK cells, facilitating immune evasion. Nonimmunologically, they promote tumor growth and metastasis through processes such as the epithelial‒mesenchymal transition, angiogenesis, and premetastatic niche formation. MDSC accumulation is closely linked to accelerated tumor progression, including resistance to both immunotherapies and conventional treatments, making these cells critical therapeutic targets. Clinical studies have demonstrated the potential of MDSC‐targeted strategies to improve treatment efficacy. However, challenges remain in achieving specificity and effectiveness in MDSC‐targeted therapies, emphasizing the need for a deeper understanding of their biology. This review summarizes the origin, classification, and biological characteristics of MDSCs, their dual roles in tumor progression, and their clinical significance. We also discuss recent advances in clinical and preclinical studies, including both traditional targeted therapies and emerging innovative strategies. By integrating current findings, we aim to provide a comprehensive perspective on the role of MDSCs in cancer and valuable insights for advancing cancer treatment and drug development. This review summarizes the origin and biological characteristics of MDSCs, focusing on their immunological and nonimmunological roles in tumor progression. It also discusses the prognostic value of MDSCs and the latest advancements in clinical trials, highlighting the potential of emerging therapeutic strategies for cancer treatment and drug development.

Interleukin-1β (IL-1β)–mediated inflammation suppresses antitumor immunity, leading to the generation of a tumor-permissive environment, tumor growth, and progression. Here, we demonstrate that nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in melanoma is linked to IL-1β production, inflammation, and immunosuppression. Analysis of cancer genome datasets (TCGA and GTEx) revealed greater NLRP3 and IL-1β expression in cutaneous melanoma samples (n = 469) compared to normal skin (n = 324), with a highly significant correlation between NLRP3 and IL-1β (P < 0.0001). We show the formation of the NLRP3 inflammasome in biopsies of metastatic melanoma using fluorescent resonance energy transfer analysis for NLRP3 and apoptosis-associated speck-like protein containing a CARD. In vivo, tumor-associated NLRP3/IL-1 signaling induced expansion of myeloid-derived suppressor cells (MDSCs), leading to reduced natural killer and CD8⁺ T cell activity concomitant with an increased presence of regulatory T (Treg) cells in the primary tumors. Either genetic or pharmacological inhibition of tumor-derived NLRP3 by dapansutrile (OLT1177) was sufficient to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth. Additionally, we observed that the combination of NLRP3 inhibition and anti–PD-1 treatment significantly increased the antitumor efficacy of the monotherapy by limiting MDSC-mediated T cell suppression and tumor progression. These data show that NLRP3 activation in melanoma cells is a protumor mechanism, which induces MDSCs expansion and immune evasion. We conclude that inhibition of NLRP3 can augment the efficacy of anti–PD-1 therapy.

Myeloid–derived suppressor cells (MDSCs) comprised a heterogeneous subset of bone marrow–derived myeloid cells, best studied in cancer research, that are increasingly implicated in the pathogenesis of pulmonary vascular remodeling and the development of pulmonary hypertension. Stem cell transplantation represents one extreme interventional strategy for ablating the myeloid compartment but poses a number of translational challenges. There remains an outstanding need for additional therapeutic targets to impact MDSC function, including the potential to alter interactions with innate and adaptive immune subsets, or alternatively, alter trafficking receptors, metabolic pathways, and transcription factor signaling with readily available and safe drugs. In this review, we summarize the current literature on the role of myeloid cells in the development of pulmonary hypertension, first in pulmonary circulation changes associated with myelodysplastic syndromes, and then by examining intrinsic myeloid cell changes that contribute to disease progression in pulmonary hypertension. We then outline several tractable targets and pathways relevant to pulmonary hypertension via MDSC regulation. Identifying these MDSC-regulated effectors is part of an ongoing effort to impact the field of pulmonary hypertension research through identification of myeloid compartment-specific therapeutic applications in the treatment of pulmonary vasculopathies.

An ideal tumor treatment is supposed to eliminate the primary tumor and simultaneously trigger the host antitumor immune responses to prevent tumor recurrence and metastasis. Herein, a liposome encapsulating phosphoinositide 3‐kinase gamma (PI3Kγ) inhibitor IPI‐549 and photosensitizer chlorin e6 (Ce6), denoted by LIC, is prepared for colon cancer treatment. LIC internalized into CT26 cells generates reactive oxygen species (ROS) under laser irradiation to cause immunogenic tumor cell death, during which immunostimulatory signals such as calreticulin are released to further induce T lymphocyte‐mediated tumor cell killing. Meanwhile, IPI‐549 transported by liposome can inhibit PI3Kγ in the myeloid‐derived suppressive cells (MDSCs), resulting in downregulation of arginase 1 (Arg‐1) and ROS to promote MDSCs apoptosis and reduce their immunosuppressive activity to CD8+ T cells. LIC‐mediated immunogenic photodynamic therapy synergizes with MDSCs‐targeting immunotherapy, which significantly inhibits tumor growth via facilitating the dendritic cell maturation and tumor infiltration of CD8+ T cells while decreasing the tumor infiltration of immunosuppressive regulatory T cells, MDSCs, and M2‐like tumor‐associated macrophages. Moreover, the synergistic therapy increases the number of effector memory T cells (TEM) in spleen, which suggests a favorable immune memory to prevent tumor recurrence and metastasis. The Ce6 and IPI‐549‐coloaded multifunctional nanodrug demonstrates high efficacy in colon cancer treatment. A liposome encapsulating phosphoinositide 3‐kinase gamma inhibitor IPI‐549 and photosensitizer chlorin e6 (Ce6) mediates immunogenic photodynamic therapy synergizing with myeloid‐derived suppressive cells (MDSCs)‐targeting immunotherapy, which significantly inhibits colon cancer growth via facilitating the dendritic cells maturation and tumor infiltration of CD8+ T cells while decreasing the tumor infiltration of immunosuppressive regulatory T cells, MDSCs, and M2‐like tumor‐associated macrophages.

Intratumoral infiltration of myeloid-derived suppressor cells (MDSCs) is known to promote neoplastic growth by inhibiting the tumoricidal activity of T cells. However, direct interactions between patient-derived MDSCs and circulating tumors cells (CTCs) within the microenvironment of blood remain unexplored. Dissecting interplays between CTCs and circulatory MDSCs by heterotypic CTC/MDSC clustering is critical as a key mechanism to promote CTC survival and sustain the metastatic process. We characterized CTCs and polymorphonuclear-MDSCs (PMN-MDSCs) isolated in parallel from peripheral blood of metastatic melanoma and breast cancer patients by multi-parametric flow cytometry. Transplantation of both cell populations in the systemic circulation of mice revealed significantly enhanced dissemination and metastasis in mice co-injected with CTCs and PMN-MDSCs compared to mice injected with CTCs or MDSCs alone. Notably, CTC/PMN-MDSC clusters were detected in vitro and in vivo either in patients’ blood or by longitudinal monitoring of blood from animals. This was coupled with in vitro co-culturing of cell populations, demonstrating that CTCs formed physical clusters with PMN-MDSCs; and induced their pro-tumorigenic differentiation through paracrine Nodal signaling, augmenting the production of reactive oxygen species (ROS) by PMN-MDSCs. These findings were validated by detecting significantly higher Nodal and ROS levels in blood of cancer patients in the presence of naïve, heterotypic CTC/PMN-MDSC clusters. Augmented PMN-MDSC ROS upregulated Notch1 receptor expression in CTCs through the ROS-NRF2-ARE axis, thus priming CTCs to respond to ligand-mediated (Jagged1) Notch activation. Jagged1-expressing PMN-MDSCs contributed to enhanced Notch activation in CTCs by engagement of Notch1 receptor. The reciprocity of CTC/PMN-MDSC bi-directional paracrine interactions and signaling was functionally validated in inhibitor-based analyses, demonstrating that combined Nodal and ROS inhibition abrogated CTC/PMN-MDSC interactions and led to a reduction of CTC survival and proliferation. This study provides seminal evidence showing that PMN-MDSCs, additive to their immuno-suppressive roles, directly interact with CTCs and promote their dissemination and metastatic potency. Targeting CTC/PMN-MDSC heterotypic clusters and associated crosstalks can therefore represent a novel therapeutic avenue for limiting hematogenous spread of metastatic disease.

The advent of immunotherapy represents a significant breakthrough in cancer treatment, with immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 demonstrating remarkable therapeutic efficacy. However, patient responses to immunotherapy vary significantly, with immunosuppression within the tumor microenvironment (TME) being a critical factor influencing this variability. Immunosuppression plays a pivotal role in regulating cancer progression, metastasis, and reducing the success rates of immunotherapy. Myeloid-derived suppressor cells (MDSCs), due to their potent immunosuppressive capabilities, emerged as major negative regulators within the TME, facilitating tumor immune evasion by modulating various immune cells. In addition to their immunosuppressive functions, MDSCs also promote tumor growth and metastasis through non-immunological mechanisms, such as angiogenesis and the formation of pre-metastatic niches. Consequently, MDSCs in the TME are key regulators of cancer immune responses and potential therapeutic targets in cancer treatment. This review describes the origins and phenotypes of MDSCs, their biological roles in tumor progression, and regulatory mechanisms, with a focus on current therapeutic approaches targeting tumor-associated MDSCs. Furthermore, the synergistic effects of targeting MDSCs in combination with immunotherapy are explored, aiming to provide new insights and directions for cancer therapy.