Transcriptional heterogeneity of tumor-associated macrophages (TAMs) has been investigated in individual cancers, but the extent to which these states transcend tumor types and represent a general feature of cancer remains unclear. We performed pan-cancer single-cell RNA sequencing analysis across nine cancer types and identified distinct monocyte/TAM composition patterns. Using spatial analysis from clinical study tissues, we assessed TAM functions in shaping the tumor microenvironment (TME) and influencing immunotherapy. Two specific TAM clusters (pro-inflammatory and pro-tumor) and four TME subtypes showed distinct immunological features, genomic profiles, immunotherapy responses, and cancer prognosis. Pro-inflammatory TAMs resided in immune-enriched niches with exhausted CD8+ T cells, while pro-tumor TAMs were restricted to niches associated with a T-cell-excluded phenotype and hypoxia. We developed a machine learning model to predict immune checkpoint blockade response by integrating TAMs and clinical data. Our study comprehensively characterizes the common features of TAMs and highlights their interaction with the TME.

Background: The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. Methods: Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m² docetaxel, 80 mg/m² oxaliplatin, 200 mg/m² calcium levofolinate, 2600 mg/m² 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. Results: Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8–42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8–35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2–89.2%), 78.8% (95% CI, 65.1–95.5%), and 70.9% (95% CI, 54.8–91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3–93.1%) and 96.9% (95% CI, 84.3–99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. Conclusions: The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

Anthracycline-based chemotherapy resistance represents a major challenge in diffuse large B-cell lymphoma (DLBCL). MiRNA and gene expression profiles (n = 47) were determined to uncover potential chemoresistance mechanisms and therapeutic approaches. An independent correlation between high expression of miRNA-363-3p and chemoresistance was observed and validated in a larger cohort (n = 106). MiRNA-363-3p was shown to reduce doxorubicin-induced apoptosis and tumor shrinkage in in vitro and in vivo experiments by ectopic expression and CRISPR/Cas9-mediated knockout in DLBCL cell lines. DNA methylation was found to participate in transcriptional regulation of miRNA-363-3p. Further investigation revealed that dual specificity phosphatase 10 (DUSP10) is a target of miRNA-363-3p and its suppression promotes the phosphorylation of c-Jun N-terminal kinase (JNK). The miRNA-363-3p/DUSP10/JNK axis was predominantly associated with negative regulation of homologous recombination (HR) and DNA repair pathways. Ectopic expression of miRNA-363-3p more effectively repaired doxorubicin-induced double-strand break (DSB) while enhancing non-homologous end joining repair and reducing HR repair. Targeting JNK and poly (ADP-ribose) polymerase 1 significantly inhibited doxorubicin-induced DSB repair, increased doxorubicin-induced cell apoptosis and tumor shrinkage, and improved the survival of tumor-bearing mice. In conclusion, the miRNA-363-3p/DUSP10/JNK axis is a novel chemoresistance mechanism in DLBCL that may be reversed by targeted therapy.

Triple-negative breast cancer (TNBC) presents significant challenges to female health owing to the lack of therapeutic targets and its poor prognosis. In recent years, in the field of molecular pathology, there has been a growing focus on the role of intra-tumoral microbial communities and metabolic alterations in tumor cells. However, the precise mechanism through which microbiota and their metabolites influence TNBC remains unclear and warrants further investigation. In this study, we analyzed the microbial community composition in various subtypes of breast cancer through 16S rRNA MiSeq sequencing of formalin-fixed, paraffin-embedded (FFPE) tissue samples. Notably, Turicibacter, a microbe associated with cancer response, exhibited a significantly higher abundance in TNBC. Similarly, mass spectrometry-based metabolomic analysis revealed substantial differences in specific metabolites, such as nutriacholic, pregnanetriol, and cortol. Furthermore, we observed significant correlations between the intra-tumoral microbiome, clinicopathological characteristics, and human epidermal growth factor receptor-2 expression(HER2). Three microbial taxa (Cytophagaceae, Conexibacteraceae, and Flavobacteriaceae) were associated with tumor-infiltrating lymphocytes(TILs), which are indicative of antitumor immunity. This study creatively utilized FFPE tissue samples to assess intra-tumoral microbial communities and their related metabolic correlations, presenting avenues for the identification of novel diagnostic biomarkers, the development of therapeutic strategies, and the early clinical diagnosis of TNBC.

Aims and Background: Esophageal cancer is the eighth most common malignancy and sixth leading cause of cancer deaths in the world. Recent studies have shown the potential role of the aryl hydrocarbon receptor (AhR) in tumor development; however, little is known about its role in esophageal squamous cell carcinoma. In the present study, we evaluated AhR expression in esophageal tumor tissues as well as cell lines and investigated the effects of AhR activation by its agonist BNF on esophageal squamous cell carcinoma invasion using Eca109 and TE-13 cells as a model. Methods: Western blotting was performed to detect the AhR and CYP1A1 protein expression. Transwell migration assays were carried out to study the effects of BNF on esophageal squamous cell carcinoma cell invasion. AhR-specific siRNA was used to knock down the expression of AhR protein. Results: Our results showed that AhR was highly expressed in esophageal squamous cell carcinoma tissues and cell lines when compared with its expression in normal tissue. AhR siRNA robustly decreased AhR protein expression in both Eca109 and TE-13 cells. BNF significantly inhibited invasion of human esophageal squamous cell carcinoma cells via activation of AhR. Conclusions: The obtained results provide critical information on the roles of BNF in mediating esophageal squamous cell carcinoma invasion. This information could be useful for future therapeutic intervention in this lethal human disease.