Targeted inhibition of STAT3 induces immunogenic cell death of hepatocellular carcinoma cells via glycolysis

Abstract

In hepatocellular carcinoma (HCC), the signal transducer and activator of transcription 3 (STAT3) is present in an overactive state that is closely related to tumour development and immune escape. STAT3 inhibition reshapes the tumour immune microenvironment, but the underlying mechanisms have not been fully clarified. We found that STAT3 inhibition could induce immunogenic cell death (ICD) of HCC cells via translocation of the “eat me” molecule calreticulin to the cell surface and a significant reduction in the expression of the “don’t eat me” molecule leucocyte surface antigen CD47. STAT3 inhibition promoted dendritic cell (DC) activation and enhanced the recognition and phagocytosis of HCC cells by macrophages. Furthermore, STAT3 inhibition prevented the expression of key glycolytic enzymes, facilitating the induction of ICD in HCC. Interestingly, STAT3 directly regulated the transcription of CD47 and solute carrier family 2 member 1 (SLC2A1; also known as GLUT1). In subcutaneous and orthotopic transplantation mouse tumour models, the STAT3 inhibitor napabucasin prevented tumour growth and induced the expression of calreticulin and the protein disulfide isomerase family A member 3 (PDIA3; also known as ERp57) but suppressed that of CD47 and GLUT1. Meanwhile, the amount of tumour‐infiltrated DCs and macrophages increased, along with the expression of costimulatory molecules. More CD4+ and CD8+ T cells accumulated in tumour tissues, and CD8+ T cells had lower expression of checkpoint molecules such as lymphocyte activation gene 3 protein (LAG‐3) and programmed cell death protein 1 (PD‐1). Significantly, the antitumour immune memory response was induced by treatment targeting STAT3. These findings provide a new mechanism for targeting STAT3‐induced ICD in HCC, and confirms STAT3 as a potential target for the treatment of HCC via reshaping the tumour immune microenvironment.

SHP-1/STAT3-Signaling-Axis-Regulated Coupling between BECN1 and SLC7A11 Contributes to Sorafenib-Induced Ferroptosis in Hepatocellular Carcinoma

“…TTI-101, a small-molecule STAT3 inhibitor that competitively targets the phosphotyrosyl peptide-binding pocket in the Src homology 2 (SH2) domain of STAT3, has shown anti-HCC activities [ 35 , 36 ] and received orphan drug designation for HCC. STAT3 inhibition by napabucasin suppresses HCC growth, probably by enhancing the “eat me” calreticulin signal, reducing the expression of the “don’t eat me” protein CD47, and triggering immunogenic cell death [ 37 ]. Suppressing STAT3 signals may also induce the polarization of anti-tumoral M1 macrophages and reshape the HCC tumor microenvironment [ 38 ].…”

Significance of immunogenic cell death-related prognostic gene signature in cervical cancer prognosis and anti-tumor immunity

“…We screened for PDIA3, a key poor prognostic regulator of ICD that binds to calreticulin and translocates to the cell surface, where calreticulin sends phagocytic signals to professional antigen-presenting cells, but CD47 strongly inhibits phagocytosis [46]. Furthermore, PDIA3 promotes transcriptional activator 3 (STAT3) to drive tumor development and immune escape [47]. In addition, STAT3 is involved in our enriched pathway results: the JAK/STAT signaling pathway, which is highly expressed in various malignancies [48].…”

STAT3 Inhibitors: A Novel Insight for Anticancer Therapy of Pancreatic Cancer

“…Immune escape and immunosuppression are among the features in TME; STAT3 in cancer cells can inhibit the activation of dendritic cells and promote enhanced metabolism of substances in the TME [ 66 ]. Immunosuppression in pancreatic cancer TME is manifested by a lack of CD8+ T-cell numbers and decreased function [ 67 ].…”