The Cancer Antioxidant Regulation System in Therapeutic Resistance.

Antioxidants play a pivotal role in neutralizing reactive oxygen species (ROS), which are known to induce oxidative stress. In the context of cancer development, cancer cells adeptly maintain elevated levels of both ROS and antioxidants through a process termed "redox reprogramming". This balance optimizes the proliferative influence of ROS while simultaneously reducing the potential for ROS to cause damage to the cell. In some cases, the adapted antioxidant machinery can hamper the efficacy of treatments for neoplastic diseases, representing a significant facet of the resistance mechanisms observed in cancer therapy. In this review, we outline the contribution of antioxidant systems to therapeutic resistance. We detail the fundamental constituents of these systems, encompassing the central regulatory mechanisms involving transcription factors (of particular importance is the KEAP1/NRF2 signaling axis), the molecular effectors of antioxidants, and the auxiliary systems responsible for NADPH generation. Furthermore, we present recent clinical trials based on targeted antioxidant systems for the treatment of cancer, assessing the potential as well as challenges of this strategy in cancer therapy. Additionally, we summarize the pressing issues in the field, with the aim of illuminating a path toward the emergence of novel anticancer therapeutic approaches by orchestrating redox signaling.

IFNα-induced BST2+ tumor-associated macrophages facilitate immunosuppression and tumor growth in pancreatic cancer by ERK-CXCL7 signaling.

Pancreatic ductal adenocarcinoma (PDAC) features an immunosuppressive tumor microenvironment (TME) that resists immunotherapy. Tumor-associated macrophages, abundant in the TME, modulate T cell responses. Bone marrow stromal antigen 2-positive (BST2+) macrophages increase in KrasG12D/+; Trp53R172H/+; Pdx1-Cre mouse models during PDAC progression. However, their role in PDAC remains elusive. Our findings reveal a negative correlation between BST2+ macrophage levels and PDAC patient prognosis. Moreover, an increased ratio of exhausted CD8+ T cells is observed in tumors with up-regulated BST2+ macrophages. Mechanistically, BST2+ macrophages secrete CXCL7 through the ERK pathway and bind with CXCR2 to activate the AKT/mTOR pathway, promoting CD8+ T cell exhaustion. The combined blockade of CXCL7 and programmed death-ligand 1 successfully decelerates tumor growth. Additionally, cGAS-STING pathway activation in macrophages induces interferon (IFN)α synthesis leading to BST2 overexpression in the PDAC TME. This study provides insights into IFNα-induced BST2+ macrophages driving an immune-suppressive TME through ERK-CXCL7 signaling to regulate CD8+ T cell exhaustion in PDAC.

Histological tumor micronecrosis in resected specimens after R0 hepatectomy for hepatocellular carcinomas is a factor in determining adjuvant TACE: A retrospective propensity score-matched study.

BACKGROUND: Tumor micronecrosis is a less investigated pathological feature of hepatocellular carcinoma (HCC). This study was aimed at evaluating the value of micronecrosis for guiding adjuvant transcatheter arterial chemoembolization (TACE) in HCC management. METHODS: We retrospectively reviewed the data of patients with HCC who underwent curative liver resection in our center from 2014 to 2018. The patients were divided into micronecrosis (+) and micronecrosis (-) groups. In each group, overall survival (OS) and disease-free survival (DFS) were compared between patients who underwent adjuvant TACE and those who did not. Propensity score matching (PSM) was conducted at a ratio of 1:1 to control selection bias. Univariate and multivariate analyses were performed to determine independent prognostic factors. Mass cytometry was applied to compare the immunological status of HCCs between the two groups. RESULTS: A total of 897 patients were included, with 417 and 480 patients in the micronecrosis (+) and micronecrosis (-) groups, respectively. No significant difference was detected in baseline parameters after PSM. In the micronecrosis (+) group, patients who underwent adjuvant TACE had significant longer OS than did those who did not (P = 0.004). However, patients in the micronecrosis (-) group did not benefit from adjuvant TACE. Although adjuvant TACE prolonged the DFS of patients with severe micronecrosis (P = 0.034), it may adversely affect the DFS of patients without micronecrosis (P = 0.131). Multivariate analysis showed that TACE was an independent prognostic factor for patients with micronecrosis but not for those without micronecrosis. The abundance of exhausted and regulatory T cells was significantly higher in patients with micronecrosis. CONCLUSIONS: For HCC patients with micronecrosis, adjuvant TACE after curative resection could improve the prognosis, while its survival benefits were limited in HCC patients without micronecrosis. TACE should be selectively performed in patients with micronecrosis, especially those with an Nscore = 2. The immunosuppressive status of HCC patients with micronecrosis may explain the effectiveness of adjuvant TACE in such scinario.