Immune Cell Landscape in the NSCLC Tumour Microenvironment: Molecular Dysregulation, Crosstalk and Insights into the CEMIP-STAT3-Mediated Immunosuppressive Axis
- 1Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumour Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- 2Hubei Key Laboratory of Tumour Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
Abstract
Immunotherapy using immune checkpoint inhibitors has yielded meaningful clinical benefits for patients diagnosed with non-small cell lung cancer (NSCLC). Many patients still develop primary or acquired treatment resistance, a problem strongly tied to immunosuppressive features of the tumour microenvironment (TME). Multiple immune cell populations within the TME, including tumour-associated macrophages, CD8+ cytotoxic T cells, regulatory T cells, Natural killer (NK) cells and myeloid-derived suppressor cells, interact via soluble mediators and cell-surface molecules. Disordered crosstalk between these cell populations promotes tumour immune escape and limits immunotherapy effectiveness. In this review, we summarise major molecular mechanisms that control immune-cell behaviour in the NSCLC TME, placing special emphasis on the Cell migration inducing hyaluronidase 1 (CEMIP)-signal transducer and activator of transcription 3 (STAT3) axis described in pre-clinical work. Tumour-produced CEMIP is reported to promote macrophage polarisation toward an M2-like suppressive phenotype, putatively via an unidentified surface receptor and downstream STAT3 activation. This phenotypic shift in turn indirectly upregulates several inhibitory receptors on CD8+ T and Natural killer (NK) lymphocytes, offering a reasonable upstream mechanistic explanation for resistance to immune-checkpoint-blockade treatment. The supposed CEMIP receptor on monocytes has not yet been identified, and the possibility of indirect effects cannot be completely ruled out. For example, ECM remodeling or intermediary cellular signalling mediated by CEMIP is a possibility; for specific discussions. These unresolved mechanistic details, together with the lack of large-scale human NSCLC cohort validation, underscore that the CEMIP-STAT3 axis remains a pre-clinical observation requiring substantial further investigation before clinical translation can be contemplated. We therefore position this review as a critical, evidence-based assessment of the CEMIP–STAT3 hypothesis, rather than as a claim that this axis is an established driver of NSCLC immunosuppression.
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BibTeX
@article{wang2026immune,
title = {{Immune Cell Landscape in the NSCLC Tumour Microenvironment: Molecular Dysregulation, Crosstalk and Insights into the CEMIP-STAT3-Mediated Immunosuppressive Axis}},
author = {Lanqing Wang and Sisi Yan and Fajian He and Conghua Xie and Rui Bai},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18213451},
url = {https://www.mdpi.com/2072-6694/18/21/3451},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Immune Cell Landscape in the NSCLC Tumour Microenvironment: Molecular Dysregulation, Crosstalk and Insights into the CEMIP-STAT3-Mediated Immunosuppressive Axis
AU - Lanqing Wang
AU - Sisi Yan
AU - Fajian He
AU - Conghua Xie
AU - Rui Bai
PY - 2026
DA - 2026/10/26
JO - Cancers
DO - 10.3390/cancers18213451
UR - https://www.mdpi.com/2072-6694/18/21/3451
AB - Immunotherapy using immune checkpoint inhibitors has yielded meaningful clinical benefits for patients diagnosed with non-small cell lung cancer (NSCLC). Many patients still develop primary or acquired treatment resistance, a problem strongly tied to immunosuppressive features of the tumour microenvironment (TME). Multiple immune cell populations within the TME, including tumour-associated macrophages, CD8+ cytotoxic T cells, regulatory T cells, Natural killer (NK) cells and myeloid-derived suppressor cells, interact via soluble mediators and cell-surface molecules. Disordered crosstalk between these cell populations promotes tumour immune escape and limits immunotherapy effectiveness. In this review, we summarise major molecular mechanisms that control immune-cell behaviour in the NSCLC TME, placing special emphasis on the Cell migration inducing hyaluronidase 1 (CEMIP)-signal transducer and activator of transcription 3 (STAT3) axis described in pre-clinical work. Tumour-produced CEMIP is reported to promote macrophage polarisation toward an M2-like suppressive phenotype, putatively via an unidentified surface receptor and downstream STAT3 activation. This phenotypic shift in turn indirectly upregulates several inhibitory receptors on CD8+ T and Natural killer (NK) lymphocytes, offering a reasonable upstream mechanistic explanation for resistance to immune-checkpoint-blockade treatment. The supposed CEMIP receptor on monocytes has not yet been identified, and the possibility of indirect effects cannot be completely ruled out. For example, ECM remodeling or intermediary cellular signalling mediated by CEMIP is a possibility; for specific discussions. These unresolved mechanistic details, together with the lack of large-scale human NSCLC cohort validation, underscore that the CEMIP-STAT3 axis remains a pre-clinical observation requiring substantial further investigation before clinical translation can be contemplated. We therefore position this review as a critical, evidence-based assessment of the CEMIP–STAT3 hypothesis, rather than as a claim that this axis is an established driver of NSCLC immunosuppression.
SN - 2072-6694
ER -