NLRP3 inflammasome was introduced as a double-edged sword in tumorigenesis and influenced immunotherapy response by modulating host immunity. However, a systematic assessment of the NLRP3-inflammasome-related genes across human cancers is lacking, and the predictive role of NLRP3 inflammasome in cancer immunotherapy (CIT) response remains unexplored. Thus, in this study, we performed a pan-cancer analysis of NLRP3-inflammasome-related genes across 24 human cancers. Out of these 24 cancers, 15 cancers had significantly different expression of NLRP3-inflammasome-related genes between normal and tumor samples. Meanwhile, Cox regression analysis showed that the NLRP3 inflammasome score could be served as an independent prognostic factor in skin cutaneous melanoma. Further analysis indicated that NLRP3 inflammasome may influence tumor immunity mainly by mediating tumor-infiltrating lymphocytes and macrophages, and the effect of NLRP3 inflammasome on immunity is diverse across tumor types in tumor microenvironment. We also found that the NLRP3 inflammasome score could be a stronger predictor for immune signatures compared with tumor mutation burden (TMB) and glycolytic activity, which have been reported as immune predictors. Furthermore, analysis of the association between NLRP3 inflammasome and CIT response using six CIT response datasets revealed the predictive value of NLRP3 inflammasome for immunotherapy response of patients in diverse cancers. Our study illustrates the characterization of NLRP3 inflammasome in multiple cancer types and highlights its potential value as a predictive biomarker of CIT response, which can pave the way for further investigation of the prognostic and therapeutic potentials of NLRP3 inflammasome.

FBXW7 (F-Box and WD Repeat Domain Containing 7) (also referred to as FBW7 or hCDC4) is a component of the Skp1-Cdc53 / Cullin-F-box-protein complex (SCF/β-TrCP). As a member of the F-box protein family, FBXW7 serves a role in phosphorylation-dependent ubiquitination and proteasome degradation of oncoproteins that play critical role(s) in oncogenesis. FBXW7 affects many regulatory functions involved in cell survival, cell proliferation, tumor invasion, DNA damage repair, genomic instability and telomere biology. This thorough review of current literature details how FBXW7 expression and functions are regulated through multiple mechanisms and how that ultimately drives tumorigenesis in a wide array of cell types. The clinical significance of FBXW7 is highlighted by the fact that FBXW7 is frequently inactivated in human lung, colon, and hematopoietic cancers. The loss of FBXW7 can serve as an independent prognostic marker and is significantly correlated with the resistance of tumor cells to chemotherapeutic agents and poorer disease outcomes. Recent evidence shows that genetic mutation of FBXW7 differentially affects the degradation of specific cellular targets resulting in a distinct and specific pattern of activation/inactivation of cell signaling pathways. The clinical significance of FBXW7 mutations in the context of tumor development, progression, and resistance to therapies as well as opportunities for targeted therapies is discussed.

Background: Immune-related adverse events (irAEs), characterized by targeted inflammation, occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). Evidence proved that the baseline peripheral blood profiles of patients at risk for severe irAEs development paralleled clinical autoimmunity. Interleukin (IL)-23 blockade with risankizumab is recommended for cases that are suffering from autoimmune disease, such as autoimmune colitis. However, currently, the role of IL-23 in irAEs onset and severity remains poorly understood. Methods: The pro-inflammatory cytokines most associated with severe irAEs onset were identified by retrospective analysis based on GSE186143 data set. To investigate the efficacy of prophylactic IL-23 blockade administration to prevent irAEs, refer to a previous study, we constructed two irAEs murine models, including dextran sulfate sodium salt (DSS)-induced colitis murine model and a combined-ICIs-induced irAEs murine model. To further explore the applicability of our findings, murine models with graft-versus-host disease were established, in which Rag2^−/−Il2rg^−/− mice were transferred with human peripheral blood mononuclear cells and received combined cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) treatment. Human melanoma cells were xenografted into these mice concomitantly. Results: Here we show that IL-23 was upregulated in the serum of patients suffering from irAEs after dual anti-CTLA-4 and anti-PD-1 treatment, and increased as a function of irAEs severity. Additionally, Augmented CD4⁺ Tems may preferentially underlie irAEs onset. Treating mice with anti-mouse IL-23 antibody concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, preserves antitumor efficacy. Moreover, in xenografted murine models with irAEs, prophylactic blockade of human IL-23 using clinically available IL-23 inhibitor (risankizumab) ameliorated colitis, hepatitis and lung inflammation, and moreover, immunotherapeutic control of tumors was retained. Finally, we also provided a novel machine learning-based computational framework based on two blood-based features—IL-23 and CD4⁺ Tems—that may have predictive potential for severe irAEs and ICIs response. Conclusions: Our study not only provides clinically feasible strategies to dissociate efficacy and toxicity in the use of combined ICIs for cancer immunotherapy, but also develops a blood-based biomarker that makes it possible to achieve a straightforward and non-invasive, detection assay for early prediction of irAEs onset.

Objective: Although many curative treatments are being applied in the clinic, a significant number of patients with liver hepatocellular carcinoma (LIHC) suffer from drug resistance. The tumour microenvironment (TME) has been found to be closely associated with resistance, suggesting that identification of predictive biomarkers related to the TME for resistance in LIHC will be very rewarding. However, there has been no study dedicated to identifying a TME-related biomarker that has the potential to predict resistance in LIHC. Methods: An integrated analysis was conducted based on data of patients with LIHC suffering from drug resistance from the TCGA database and four GEO datasets. Subsequently, we also validated the expression levels of the identified genes in paraffin-embedded LIHC samples by immunohistochemistry. Results: In this study, we developed a robust and acute TME-related signature consisted of five immune-related genes (FABP6, CD4, PRF1, EREG and COLEC10) that could independently predict both the RFS and OS of LIHC patients. Moreover, the TME-related signature was significantly associated with the immune score, immune cytolytic activity (CYT), HLA, interferon (IFN) response and tumour-infiltrating lymphocytes (TILs), and it might influence tumour immunity mainly by affecting B cells, CD8⁺ T cells and dendritic cells. Furthermore, our analysis also indicated that the TME-related signature was correlated with the immunotherapy response and had an enormous potential to predict sorafenib resistance in LIHC. Conclusion: Our findings demonstrated a TME-related signature which can independently predict both the RFS and OS of LIHC patients, highlighting the predictive potential of the signature for immunotherapy response and sorafenib resistance, potentially enabling more precise and personalized sorafenib treatment in LIHC in the future.

High mortality of patients with cervical cancer (CC) stresses the imperative of prognostic biomarkers for CC patients. Additionally, the vital status of post‐translational modifications (PTMs) in the progression of cancers has been reported by numerous researches. Therefore, the purpose of this research was to dig a prognostic signature correlated with PTMs for CC. We built a five‐mRNA (GALNTL6, ARSE, DPAGT1, GANAB and FURIN) prognostic signature associated with PTMs to predict both disease‐free survival (DFS) (hazard ratio [HR] = 3.967, 95% CI = 1.985‐7.927; P < .001) and overall survival (HR = 2.092, 95% CI = 1.138‐3.847; P = .018) for CC using data from The Cancer Genome Atlas database. Then, the robustness of the signature was validated using GSE44001 and the Human Protein Atlas (HPA) database. CIBERSORT algorithm analysis displayed that activated CD4 memory T cell was also an independent indicator for DFS (HR = 0.426, 95% CI = 0.186‐0.978; P = .044) which could add additional prognostic value to the signature. Collectively, the PTM‐related signature and activated CD4 memory T cell can provide new avenues for the prognostic predication of CC. These findings give further insights into effective treatment strategies for CC, providing opportunities for further experimental and clinical validations.