Aug 2026· Cancer Letters· pp.
218803
· 0 citations· 267 references
Medicine
TL;DR
Together, current evidence indicates that MDSCs represent context-dependent therapeutic nodes, while functional reprogramming, spatially resolved profiling, and patient stratification may improve immunotherapy outcomes.
Abstract
Tumor microenvironment (TME)-induced immunosuppression is a major driver of cancer treatment failure and resistance to immunotherapy. Myeloid-derived suppressor cells (MDSCs) are not only pivotal suppressors of effector immune responses but also central organizers of tumor-supportive metabolic, stromal, and cellular crosstalk. This review systematically summarizes the origin and phenotypic characteristics of MDSCs and the mechanisms governing their recruitment, expansion, and activation within the TME. This review integrates current knowledge of MDSC biology through two complementary frameworks. One framework highlights the bidirectional interactions between MDSCs and immune, tumor, stromal, endothelial, and adipocyte compartments. The other classifies therapeutic approaches according to their mechanisms and translational relevance, including combinations with immunotherapy. We further evaluate clinical translation, including lessons from unsuccessful or inconclusive trials, biomarker gaps, and rational combination strategies. Together, current evidence indicates that MDSCs represent context-dependent therapeutic nodes, while functional reprogramming, spatially resolved profiling, and patient stratification may improve immunotherapy outcomes.
Despite the remarkable progress in cancer treatment, drug resistance and immune escape still severely limit clinical efficacy, largely due to tumor-induced immunosuppression. The main driver of this suppressive environment is myeloid-derived suppressor cells (MDSCs). Tumor-derived cytokines and chemokines can induce the expansion, activation, and recruitment of MDSCs, enabling them to effectively protect tumor cells from being recognized and cleared by immune cells by establishing an immunosuppressive barrier in peripheral lymphoid organs and the tumor microenvironment (TME). Upon arrival in the TME, MDSCs may alter their gene expression patterns through metabolic reprogramming, undergo skewed differentiation toward tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs), and initiate immunosuppression to promote tumor growth. Furthermore, they can shape an environment conducive to tumor development and metastasis through various nonimmune mechanisms. Currently, the overall understanding of the systematic integration of MDSC biological properties into therapeutic strategies remains underdeveloped. Therefore, in this review, we systematically summarize: (i) the classification and identification of MDSCs; (ii) their biological properties in the context of tumors and autoimmune diseases; (iii) tumor-promoting effects; (iv) genetic and signaling pathway regulatory mechanisms; (v) differentiation skewing in the TME; and (vi) cellular interactions with the TME. We also propose the clinical potential of MDSC-based predictive and prognostic biomarkers and outline strategies for targeting MDSCs for oncotherapy.
Rong-Jun Deng, Xiu-Yun Bai, Jue Yang et al.· Signal Transduction and Targ...· 0 citations
Tumor microenvironment-resident immunosuppressive cells-comprising myeloid-derived suppressor cells, regulatory T cells, and tumor-associated macrophages-constitute primary obstacles to effective cancer immunotherapy. Advances in single-cell and spatial multi-omics have uncovered their substantial functional heterogeneity, tissue-adaptive reprogramming, and organ-specific architectures distinguishing primary tumors from metastatic lesions. Beyond canonical immune checkpoint pathways, non-canonical regulatory layers--including metabolic-immune crosstalk, epigenetic regulation, microbiome-mediated distant signaling, and therapy-induced adaptive remodeling-further reinforce treatment resistance. Based on these mechanistic insights, systematic synergistic strategies have been developed, such as multi-pathway checkpoint blockade, ADC-immunotherapy combinations, temporally and spatially optimized conventional therapies, and targeted agents that deplete or reprogram suppressive populations. Emerging biomarkers, repurposed pharmaceuticals, and pan-cancer therapeutic principles are refining patient stratification and combination regimens. This review offers a comprehensive framework for understanding and surmounting immunosuppressive barriers in cancer therapy.
Meng-Meng Liu, Yi-Chen Zhu, He-Miao Liang et al.· Frontiers in Immunology· 0 citations
Targeting the mechanisms regulating Treg recruitment, stability, or suppressive function may represent a promising strategy to enhance the efficacy of immunotherapies including Bacillus Calmette–Guérin therapy.
Yusuke Fukiage, Nodoka Okubo, M. Taga et al.· Frontiers in Molecular Biosc...· 0 citations
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature
myeloid cells that play a key role in cancer progression by promoting immune evasion, enabling tumor cells to escape immune destruction, and establishing an immunosuppressed tumor microenvironment (TME). They inhibit anti-tumor immunity through several methods, such as blocking T-cell
activation, altering dendritic cell function, and interacting with other populations of immune regulatory cells. A growing body of evidence shows that MDSCs contribute to tumor expansion, metastasis,
and resistance to immunotherapy at a significant rate. MDSCs are located at the center of immune
suppression in the TME, prompting researchers to target MDSCs in the hope of developing effective
therapeutic agents. Researchers are actively investigating strategies to deplete, block, or prevent the
recruitment of MDSCs within the TME to restore immune function within the TME. Several types of
therapies, including but not limited to small molecules, monoclonal antibodies, and combination therapies, are being evaluated, with a focus on the use of immune checkpoint inhibitors in conjunction
with the aforementioned therapies. Early studies have shown promising results; however, significant
challenges remain, including MDSC plasticity, tumor adaptation, off-target effects, and safety concerns. The objective of this review is to provide a complete overview of the biology, function, and
clinical implications of MDSCs in cancer. In addition, an analysis of current and future therapies targeting MDSCs is presented, focusing on the importance of MDSC heterogeneity in advancing personalized immunotherapies and improving patient outcomes.
S. Mali, Prajakta R. Patil, S. Nangare et al.· Current Cancer Therapy Revie...· 0 citations
Immune checkpoint blockade has redefined cancer therapy, yet durable responses remain constrained by resistance states that arise from coordinated tumor-cell, immune, stromal, vascular, lymphatic, and metabolic programs rather than from a single defective pathway. This review develops a translational framework in which tumor-intrinsic immune invisibility, myeloid and regulatory lymphocyte suppression, defective dendritic-cell priming, stromal and vascular exclusion, lymphatic control of antigen drainage, metabolic stress, and ILC2/type 2 immune plasticity are interpreted as interdependent ecosystem states. We discuss therapeutic strategies that reprogram these states, including myeloid and Treg modulation, stromal and vascular remodeling, preservation or restoration of productive lymphatic communication, cytokine and metabolic interventions, alternative checkpoint blockade, oncolytic viruses, vaccines, engineered cell therapies, and nanomedicine-enabled local delivery. Emphasis is placed on the lessons of failed or modestly effective trials, which show that biologically plausible interventions often fail when the dominant resistance bottleneck is not defined, tissue target engagement is not verified, or treatment sequence is not matched to the immune architecture of the tumor. We propose that future progress will depend on ecosystem-matched combinations guided by spatial biomarkers, on-treatment pharmacodynamics, and adaptive trial designs capable of linking mechanism to clinical decision-making.
The immunosuppressive tumor microenvironment (TME), orchestrated largely by tumor -infiltrating regulatory T cells (TI -Tregs), represents a critical barrier to effective cancer immunotherapy. This review focuses on the chemokine receptor CCR8, which has recently emerged as a highly promising and specific target for therapeutic intervention due to its preferential and stable expression on highly suppressive TI -Treg subsets. We synthesize current evidence demonstrating that CCR8 is selectively upregulated on TI -Tregs across multiple solid tumor types, where its expression correlates with poor patient prognosis and resistance to immune checkpoint inhibitors (ICIs). This expression pattern —enriched within the tumor but minimal in peripheral blood and normal tissues —provides a compelling rationale for tumor -selective targeting. We critically examine the primary therapeutic strategies under development, including ADCC -enhanced monoclonal antibodies, which have shown the most clinical promise, alongside bispecific antibodies and small molecule antagonists. While early -phase clinical trials report encouraging safety and on -target pharmacodynamic activity, the field faces significant challenges. These include unresolved questions regarding CCR8's functional role versus its value as a targeting biomarker, a lack of validated predictive biomarkers for patient stratification, and the physical barriers to effective drug delivery in solid tumors. This review aims to provide a comprehensive and nuanced understanding of CCR8 biology and to outline the key steps necessary for the successful clinical translation of CCR8-targeted therapies.
