Pancreatic cancer continues to represent one of the most aggressive and therapeutically challenging malignancies, largely due to its late diagnosis, high metastatic potential, and resistance to conventional therapies. Recent findings highlight the multifaceted involvement of HMGB1 (High Mobility Group Box 1) in both tumor-promoting mechanisms and immune modulation, making it a critical molecular node in pancreatic cancer biology
HMGB1 as a driver of autophagy and tumor progression
In a recent study, PPM1G, a serine/threonine phosphatase, was identified as a novel oncogenic factor in pancreatic ductal adenocarcinoma (PDAC). Mechanistically, PPM1G enhances macroautophagy by directly upregulating HMGB1, which in turn sustains tumor growth both in vitro and in vivo.
HMGB1protein has an intracellular role in supporting metabolic adaptation and survival pathways in pancreatic cancer cells, positioning it as a potential target for therapies aimed at disrupting tumor autophagy.
HMGB1 as a mediator of immunogenic cell death and TME remodeling
A second study explored the effects of local ablative therapies in an orthotopic murine model of PDAC. The intervention triggered rapid tumor necrosis, accompanied by a significant rise in circulating HMGB1, marking the onset of acute inflammation. This HMGB1 release acted as a damage-associated molecular pattern (DAMP), enhancing myeloid cell recruitment and activation, and promoting antigen presentation via increased MHC class II expression.
Elevated plasma HMGB1 and neutrophil-to-lymphocyte ratio (NLR) following ablation correlated with prolonged time to progression, highlighting the translational relevance of HMGB1 as a prognostic biomarker of immunogenic response.
The functional duality of HMGB1 presents a strategic opportunity: targeting intracellular HMGB1 to disrupt tumor-supportive processes, while harnessing its extracellular role to boost immunogenic responses and improve the effectiveness of immunotherapy.
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Read the full articles about the studies:
www.sciencedirect.com/science/article/abs/pii/S0898656824003103
www.pubmed.ncbi.nlm.nih.gov/39580047/
