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Purpose: Leukaemia remains a major contributor to global mortality, representing a significant health risk for a substantial number of cancer patients. Despite notable advancements in the field, existing treatments frequently exhibit limited efficacy or recurrence. Here, we explored the potential of abolishing HVEM (herpes virus entry mediator, TNFRSF14) expression in tumours as an effective approach to treat acute lymphoblastic leukaemia (ALL) and prevent its recurrence. Methods: The clinical correlations between HVEM and leukaemia were revealed by public data analysis. HVEM knockout (KO) murine T cell lymphoblastic leukaemia cell line EL4 were generated using CRISPR-Cas9 technology, and syngeneic subcutaneous tumour models were established to investigate the in vivo function of HVEM. Immunohistochemistry (IHC), RNA-seq and flow cytometry were used to analyse the tumour immune microenvironment (TIME) and tumour draining lymph nodes (dLNs). Immune functions were investigated by depletion of immune subsets in vivo and T cell functional assays in vitro. The HVEM mutant EL4 cell lines were constructed to investigate the functional domain responsible for immune escape. Results: According to public databases, HVEM is highly expressed in patients with ALL and acute myeloid leukemia (AML) and is negatively correlated with patient prognosis. Genetic deletion of HVEM in EL4 cells markedly inhibited tumour progression and prolonged the survival of tumour-bearing mice. Our experiments proved that HVEM exerted its immunosuppressive effect by inhibiting antitumour function of CD8+ T cell through CRD1 domain both in vivo and in vitro. Additionally, we identified a combination therapy capable of completely eradicating ALL tumours, which induces immune memory toward tumour protection. Conclusions: Our study reveals the potential mechanisms by which HVEM facilitates ALL progression, and highlights HVEM as a promising target for clinical applications in relapsed ALL therapy. [ABSTRACT FROM AUTHOR]

The immune checkpoint programmed death receptor 1 (PD‐1) and programmed death ligand 1 (PD‐L1) are biologically important immunosuppressive molecules, and the PD‐L1/PD‐1‐mediated signalling pathway is currently considered one of the main mechanisms of tumour escape immune surveillance. PD‐L1 is highly expressed on the cytomembrane of tumour cell and binds to PD‐1 receptor of activated T cells. This interaction activates PD‐L1/PD‐1 downstream signal transduction, inhibiting T cells anti‐tumour activity. Therefore, inhibitors of PD‐L1/PD‐1 activation, showing significant efficacy in some types of tumours, have been widely approved in clinical tumour therapy. Recent research on PD‐L1/PD‐1 signalling pathway regulation has shown post‐translational modifications (PTMs) form of PD‐L1 or PD‐1, including glycosylation, ubiquitination, phosphorylation, and acetylation, which may play an important role in PD‐L1/PD‐1 signalling pathway regulation and anti‐tumour function of T cells. In this review, we focused on PTMs of PD‐L1/PD‐1 research and potential applications in tumour immunotherapy. [ABSTRACT FROM AUTHOR]