Background: In addition to their established action of synthetic lethality in tumor cells, poly(ADP-ribose) polymerase inhibitors (PARPis) also orchestrate tumor immune microenvironment (TIME) that contributes to suppressing tumor growth. However, it remains not fully understood whether and how PARPis trigger tumor-targeting immune responses. Methods: To decode the immune responses reshaped by PARPis, we conducted T-cell receptor (TCR) sequencing and immunohistochemical (IHC) analyses of paired clinical specimens before and after niraparib monotherapy obtained from a prospective study, as well as ID8 mouse ovarian tumors. To validate the induction of immunogenic cell death (ICD) by PARPis, we performed immunofluorescence/IHC staining with homologous recombination deficiency tumor cells and patient-derived xenograft tumor tissues, respectively. To substantiate that PARPis elicited tumor cell pyroptosis, we undertook comprehensive assessments of the cellular morphological features, cleavage of gasdermin (GSDM) proteins, and activation of TNF-caspase signaling pathways through genetic downregulation/depletion and selective inhibition. We also evaluated the critical role of pyroptosis in tumor suppression and immune activation following niraparib treatment using a syngeneic mouse model with implanting CRISPR/Cas9 edited Gsdme^{−/ −} ID8 tumor cells into C57BL/6 mice. Results: Our findings revealed that PARPis augmented the proportion of neoantigen-recognized TCR clones and TCR clonal expansion, and induced an inflamed TIME characterized by increased infiltration of both innate and adaptive immune cells. This PARPis-strengthened immune response was associated with the induction of ICD, specifically identified as pyroptosis, which possessed distinctive morphological features and GSDMD/E cleavage. It was validated that the cleavage of GSDMD/E was due to elevated caspase 8 activity downstream of the TNFR1, rather than FAS and TRAIL-R. On PARP inhibition, the NF-κB signaling pathway was activated, leading to increased secretion of TNF-α and subsequent initiation of the TNFR1–caspase 8 cascade. Impeding pyroptosis through the depletion of Gsdme significantly compromised the tumor-suppressing effects of PARP inhibition and undermined the anti-immune response in the syngeneic ID8 mouse model. Conclusions: PARPis induce a specific type of ICD called pyroptosis via TNF–caspase 8–GSDMD/E axis, resulting in an inflamed TIME and augmentation of tumor-targeting immune responses. These findings deepen our understanding of PARPis activities and point toward a promising avenue for synergizing PARPis with immunotherapeutic interventions. Trial registration number: NCT04507841.

Phagosome- and xenophagosome-lysosome systems play a critical role in the defense of pathogenic bacteria, such as Salmonella and S. aureus, in macrophages. A great part of the bacteria escapes from the digestion and can survive through some mechanisms that are still poorly understood and which require further exploration. Here we identified that Salmonella inhibited the expression and activation of TFEB to blunt the functions of lysosomes and defense of clearance by activating caspase-1. The expression and activation of TFEB were enhanced early under the infection of S. aureus, which was followed by shrinkage to weaken lysosomal functions due to the delayed activation of ERK, mTOR, and STAT3. Thus, we have identified novel escape mechanisms for Salmonella and S. aureus to deepen and strengthen our strategies fighting with pathogens.

Background: Immunotherapy is the most promising treatment in triple-negative breast cancer (TNBC), and its efficiency is largely dependent on the intra-tumoral immune cells infiltrations. Thus, novel ways to assist immunotherapy by increasing immune cell infiltrations were highly desirable.Methods: To find key immune-related genes and discover novel immune-evoking molecules, gene expression profiles of TNBC were downloaded from Gene Expression Omnibus (GEO). Single-sample gene set enrichment analysis (ssGSEA) and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identified hub genes. The CMap database was used subsequently to predicate potential drugs that can modulate the overall hub gene expression network. In vitro experiments were conducted to assess the anti-tumor activity and the pyroptosis phenotypes induced by GW-8510.Results: Gene expression profiles of 198 TNBC patients were downloaded from GEO dataset GSE76124, and ssGSEA was used to divide them into Immune Cell Proficiency (ICP) group and Immune Cell Deficiency (ICD) group. Hub differential expressed gene modules between two groups were identified by WGCNA and then annotated by Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. A cyclin-dependent kinase (CDK) 2 inhibitor, GW-8510 was then identified by the CMap database and further investigated. Treatment with GW-8510 resulted in potent inhibition of TNBC cell lines. More importantly, in vitro and in vivo studies confirmed that GW-8510 and other CDK inhibitors (Dinaciclib, and Palbociclib) can induce pyroptosis by activating caspase-3 and GSDME, which might be the mechanism for their immune regulation potentials.Conclusion: GW-8510, as well as other CDK inhibitors, might serve as potential immune regulators and pyroptosis promotors in TNBC.

With the development of precision medicine, targeted therapy has attracted extensive attention. Poly(ADP‑ribose) polymerase inhibitors (PARPi) are critical clinical drugs designed to induce cell death and are major antitumor targeted agents. However, preclinical and clinical data have revealed the limitations of PARPi monotherapy. Therefore, their combination with other targeted drugs has become a research hotspot in tumor treatment. Recent studies have demonstrated the critical role of small molecular inhibitors in multiple haematological cancers and solid tumors via cellular signalling modulation, exhibiting potential as a combined pharmacotherapy. In the present review, studies focused on small molecular inhibitors targeting the homologous recombination pathway were summarized and clinical trials evaluating the safety and efficacy of combined treatment were discussed.

Background: Annually, breast cancer (BC) is the most common newly diagnosed cancer in females. The relatively crude measures of the molecular phenotypes of BC have not provided a comprehensive understanding of its molecular architecture. To a certain extent, this has resulted in many patients being over- or undertreated. Therefore, novel biomarkers that help to improve patients’ outcomes are required. The potassium channel tetramerization domain containing 12 (KCTD12) is one such candidate. Methods: Ribonucleic acid-sequencing (RNA-Seq) filings along with corresponding clinical information of BC samples were obtained from The Cancer Genome Atlas (TCGA) program databases to evaluate the associations between KCTD12 expression levels and clinical features. The prognostic value of KCTD12 in patients was examined by Kaplan-Meier survival analysis and PrognoScan database analysis. To identify the main functions of KCTD12 in BC, we performed gene set enrichment analysis (GSEA) in BC samples and cell lines. The correlations between KCTD12 expression and tumor-infiltrating lymphocyte quantities was confirmed using two online tools: Tumor Immune Estimation Resource and the Gene Expression Profiling Interaction Analysis 2. Results: KCTD12 expression was significantly decreased in cancer samples compared to normal samples, and was lowly expressed in aggressive disease relative to initial disease. Patients with lower KCTD12 expression levels showed a shorter overall survival and a shorter recurrence-free survival, indicating a worse prognosis. We found that genes of BC in the high-KCTD12 expression group were enriched in immune response pathways. Finally, the positive correlations between the expression of tumor-infiltrating lymphocytes, programmed cell-death ligand 1 (PD-L1), and programmed cell-death protein 1 (PD-1), and KCTD12 expression were confirmed. Conclusions: KCTD12 can be considered a biomarker to predict the prognosis of BC patients. KCTD12 may also help to predict patient response to PD-L1 or PD-1 inhibitor treatment.