Immune Cells Turned Accomplices: How the Body’s Defenses Help Cancer Spread

Metastasis, not the primary tumor itself, is what kills most people with cancer, and a new review argues that the immune system is far more deeply implicated in that deadly process than the classical idea of failed immune surveillance suggests. Writing in Frontiers in Oncology, a team of researchers from the First Naval Hospital of Southern Theater Command in Zhanjiang, China, systematically lays out how T cells, macrophages, neutrophils, B cells, natural killer cells, and dendritic cells can each be reprogrammed by tumors into active promoters of metastatic spread. The work, a narrative review of literature published between January 2010 and August 2026, synthesizes findings from studies using mouse models, patient specimens, single-cell RNA sequencing, and spatial transcriptomics to build what the authors call a systematic framework for understanding immune cell mechanisms in tumor metastasis.

The review’s central premise is a conceptual shift. Over the past decade, aided by technologies such as single-cell sequencing, spatial transcriptomics, and high-resolution in vivo imaging, the field has moved away from a “tumor cell centric” view toward a “tumor microenvironment ecosystem” model. In this ecosystem, immune cells are among the most plastic components: under the influence of tumor-derived cytokines, chemokines, and metabolites, they can acquire pro-metastatic phenotypes and participate in essentially every stage of the invasion-metastasis cascade, from detachment and local invasion through circulation, distant organ arrest, extravasation, and final colonization.

T cells, nominally the backbone of adaptive anti-tumor immunity, illustrate this duality. The review describes three forms of T cell dysfunction that promote metastasis: exhaustion, senescence, and metabolic restriction. Exhausted CD8+ T cells overexpress inhibitory receptors such as PD-1, CTLA-4, and TIM-3 while losing cytokine secretion capacity, leaving them unable to clear disseminated tumor cells. Metabolic stress within metastatic foci, including hypoxia, glucose depletion, lactate accumulation, and oxidative lipids, impairs T cell mitochondrial function. Strikingly, the authors cite evidence that tumor cells can transport mitochondria loaded with reactive oxygen species into T cells through tunneling nanotubes or extracellular vesicles, accelerating T cell aging and functional loss, a mechanism they suggest could become a target for improving immunotherapy.

Regulatory T cells emerge as what the review calls the hub of immune suppression. Citing work by Kahn and colleagues, the authors describe how Tregs in tumor-draining lymph nodes express high levels of the IL-2 receptor and competitively deplete interleukin-2 from the microenvironment. Starved of this signal, CD8+ T cells fail to activate and express almost no granzyme-B or perforin, the molecular machinery of cell killing. Lymph nodes, meant to be immune outposts, thereby become vulnerable points where metastasizing cancer cells can survive and establish new foci. Tregs also secrete IL-10 and TGF-beta, which can drive epithelial-mesenchymal transition, the process by which tumor cells gain migratory and invasive properties, and they collaborate with macrophages and myeloid suppressor cells to construct immunosuppressive niches.

Tumor-associated macrophages receive the most extensive treatment in the review, spanning every stage of metastasis. Recruited as circulating monocytes by tumor-secreted CCL2 and polarized toward an M2-like state by signals such as IL-4 and GM-CSF, these macrophages promote epithelial-mesenchymal transition through TGF-beta, Wnt, and IL-6 secretion; degrade the extracellular matrix with matrix metalloproteinases; drive abnormal angiogenesis and lymphangiogenesis through VEGF and related factors; and suppress T cells via PD-L1 expression, IDO and arginase-mediated nutrient depletion, and even autophagic degradation of their own MHC-I molecules through a Parkin-dependent pathway. In pre-metastatic niches, they recruit further suppressive cells, foster chronic inflammation with TNF-alpha, IL-1beta, and S100A8/A9, and increase vascular permeability to ease tumor cell extravasation. The authors caution, however, that macrophages are highly heterogeneous, often expressing mixtures of M1 and M2 genes, and that spatial distribution within tumors may predict prognosis better than simple phenotype labels.

Myeloid-derived suppressor cells, or MDSCs, are portrayed as the main force creating immune privilege for spreading tumor cells. They deplete arginine via Arg-1, produce reactive oxygen species and nitric oxide that induce T cell apoptosis, and drive durable T cell exhaustion through PD-L1, iNOS, and Arg-1 signaling amplified by TGF-beta1. In the bloodstream, the review highlights evidence that PMN-MDSCs form clusters with circulating tumor cells via ROS and Notch/Nodal signaling; these clusters physically shield tumor cells from cytotoxic T cells and natural killer cells, inhibit anoikis, and may facilitate adhesion to distant vessel walls. Within pre-metastatic niches, MDSCs secrete MMP2 and MMP9 to remodel matrix and release sequestered growth factors, priming organs for colonization.

Neutrophils, the review argues, act at all three critical stages of metastasis. At the primary tumor, they induce EMT, remodel matrix, and promote angiogenesis; neutrophil elastase entering breast cancer cells degrades IGFBP-2, freeing IGF-1 to activate pro-migratory signaling, while neutrophil extracellular traps ensnare tumor cells and degrade matrix components. In circulation, CTC-neutrophil aggregates, formed through chemokine axes, adhesion molecules, and CD47-SIRPalpha interactions, carry higher metastatic potential than single tumor cells and are associated with poor prognosis in breast, gastric, and liver cancers. In distant organs, N2-polarized neutrophils build immunosuppressive pre-metastatic niches and, through NETs engaging integrins on dormant tumor cells, can reactivate quiescent cells via FAK/ERK signaling, waking micrometastases from dormancy.

The review also complicates two cell types traditionally seen as purely protective. B cells, while capable of antitumor antibody production and antigen presentation, include regulatory subsets that suppress CD8+ T cell function in an IL-10-dependent manner, promote lung metastasis in mouse breast cancer models, and, through IgG engaging activating Fc-gamma receptors on myeloid cells, accelerate metastasis in squamous cell carcinoma models, an effect abolished in Fc-gamma-R-deficient mice. Natural killer cells, long considered frontline metastasis suppressors, can be reprogrammed into tumor-associated NK cells that compete with CD8+ T cells for IL-2 and type I interferons or form physical barriers blocking T cell infiltration, as reported in melanoma studies. The authors are explicit that these TANK findings come from specific tumor models and immunotherapy contexts and lack independent validation across cancer types, so they remain an emerging hypothesis rather than a universal paradigm.

Dendritic cells complete the picture. The review describes mature dendritic cells enriched in immunoregulatory molecules, or mregDCs, which express PD-L1 and IDO1 while lacking co-stimulatory molecules, and plasmacytoid DCs that induce regulatory T cells through IL-10 secretion. In cervical cancer, aberrant sialylation on epithelial cells converts conventional DCs into tolerant phenotypes that suppress T cells via Siglec-10 and galectin-9 signaling. Even dendritic cell-derived extracellular vesicles show dual behavior, capable of both activating anti-tumor immunity and, when reprogrammed by the tumor microenvironment, conveying Wnt/beta-catenin signals that enhance metastasis.

The authors are candid about the field’s limitations. Most supporting studies rely on animal models, and significant differences in immune cell function between mice and humans challenge clinical translation. The same cell type can perform opposite functions at different metastatic stages, making simple pro-tumor versus anti-tumor binaries inadequate, and immune microenvironment heterogeneity across metastatic sites complicates mechanistic understanding. The review itself explicitly notes that it did not undergo pre-registration or dual-blind screening and therefore does not qualify as a systematic review. Looking forward, the authors call for single-cell sequencing, spatial transcriptomics, and in vivo imaging to resolve immune cell heterogeneity across metastatic stages and organs, and they flag open questions including organ-specific microenvironment differences and host factors such as immunosenescence and obesity. What the synthesis makes clear is that metastasis is not merely tumor cells escaping a passive defense system, but a process in which the immune system itself, remodeled cell by cell, becomes part of the machinery of spread.

Subject of Research: How immune cells are reprogrammed to promote tumor metastasis

Article Title: The pro-metastatic effect and mechanism of immune cells in tumor metastasis

Article References: Geng, S., Liang, H., Lu, K., Deng, C., Bao, D., & Xu, H. (2026). The pro-metastatic effect and mechanism of immune cells in tumor metastasis. Frontiers in Oncology, 16, Article 2007187. https://doi.org/10.3389/fonc.2026.2007187

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.2007187

Keywords: tumor metastasis, tumor microenvironment, tumor-associated macrophages, regulatory T cells, myeloid-derived suppressor cells, neutrophils, regulatory B cells, natural killer cells, dendritic cells, pre-metastatic niche, immune suppression, immune checkpoint blockade