CD44-galectin-9 and TGF-β-Smad3 pathways form an autocrine loop which facilitates human cancer cells to self-regulate their immune evasion machinery

ORCID

Document Type

Article

Abstract

Human cancer cells and malignant tumours operate immune evasion machinery, which consists of a set of cross-linked biochemical pathways that suppress the activities of immune cells, such as cytotoxic T cells and natural killer cells. Recent evidence demonstrated that the immune evasion machinery operated by human cancer cells is self-sustaining. However, the mechanisms underlying self-regulation of cancer immune evasion networks remain to be understood. Here we report for the very first time that the cell surface receptor CD44 acts as an enhancer of immune evasion activity in human cancer cells rather than an immune checkpoint per se . Furthermore, upon interaction with galectin-9, CD44 was found to alter cell membrane potential and induce the secretion of TGF-β. Secreted TGF-β displays autocrine and paracrine activities following TGF-β receptor (TGFBR) engagement, which was shown to then activate the Smad3 transcriptional pathway. CD44 complexed to galectin-9 allosterically enhances activity of the TGFBR complex and this was shown to substantially amplify the expression of immune checkpoint proteins crucially associated with suppressing the anti-cancer activities of cytotoxic lymphoid cells. We also demonstrated that this is a fundamental pathway used by human embryos to prevent immune rejection and by innate immune cells to facilitate anti-bacterial innate immune response. Cancer cells and malignant tumours hijack and successfully adapt this fundamental pathway to escape immune surveillance and suppress anti-cancer immune reactions. As such, this autocrine loop allows for the self-regulation of immune evasion networks operated by cancer cells and can be considered as a promising target for highly efficient immunotherapy of cancer.

Publication Date

2026-09-16

Publication Title

Cancer Letters

Volume

660

ISSN

0304-3835

Acceptance Date

2026-09-16

Deposit Date

2026-10-05

Embargo Period

2027-09-16

Funding

This work was supported by the University of Kent-CSC (China Scholarship Council) scholarship (XL), KinderInsel grant [grant number 2022-003 to EF-K and SB] and Diamond Light Source Ltd for funding projects [grant numbers SM36941, SM38189]. Lung cancer experiments (SX) were supported by Tianjin Health Research Project (TJWJ2023XK005) and Tianjin Science and Technology Plan Project (24ZXGZSY00010). LU was supported by the Foundation for Liver Research. The authors would like to thank all the staff at King's College Hospital Liver Histopathology Department and at King's College Hospital Liver Surgical theatres for their support to the study.

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This item is under embargo until 16 September 2027

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