Background Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that develop postnatally in non-lymphoid tissues and are associated with pathological conditions. TLS typically comprise B-cell follicles containing and are encompassed by T- cell zones and dendritic cells. The prognostic and predictive value of TLS in the tumor microenvironment (TME) as potential mediators of antitumor immunity have gained interest. However, the precise relationship between localization and maturation of TLS and the clinical outcome of their presence in clear cell renal cell carcinoma (ccRCC) is yet to be elucidated. Methods Immunohistochemistry and multispectral fluorescence were used to evaluate the TLS heterogeneity along with TME cell-infiltrating characterizations. A thorough investigation of the prognostic implications of the TLS heterogeneity in 395 patients with ccRCC from two independent cohorts was conducted. Associations between TLS heterogeneity and immunologic activity were assessed by quantifying the immune cell infiltration. Results Infiltrated TLS were identified in 34.2% of the ccRCC samples (N=395). These TLS were found to be tumor-proximal, tumor-distal, or both in 37.8%, 74.1%, and 11.9% of the TLS-positive cases, respectively. A higher proportion of early TLS was found in tumor-distal TLS (p=0.016), while tumor-proximal TLS primarily comprised secondary follicle-like structures (p=0.004). In the main study cohort (Fudan University Shanghai Cancer Center, N=290), Kaplan-Meier analyses revealed a significant correlation between the presence of tumor-proximal TLS and improved progression-free survival (PFS, p0.80). Additionally, ccRCC samples with tumor-distal TLS enriched with primary follicle-like TLS exhibited higher programmed death-ligand 1 tumor-associated macrophages levels and regulatory T cells infiltration in the tumor-distal region, indicative of a suppressive TME. Conclusion This study for the first time elucidates the impact of TLS localization and maturation heterogeneities on the divergent clinical outcomes of ccRCC. The findings reveal that most TLS in ccRCC are located in the tumor-distal area and are associated with immature, immunosuppressive characterizations. Furthermore, our findings corroborate previous research demonstrating that tumor-proximal TLS were associated with favorable clinical outcomes.

Background: Immunotherapy has revolutionized cancer treatment and holds great potential for them, including metastatic clear cell renal cell carcinoma (ccRCC). However, immune resistance remains a major obstacle, limiting its efficacy and durability. Understanding the mechanisms of immune tolerance in the tumor microenvironment (TME) is pivotal for overcoming these challenges and enhancing therapeutic outcomes.

Clear cell renal cell carcinoma (ccRCC) is the most common malignant type of kidney cancer. The present study aims to explore the underlying mechanism and potential targets of the traditional Chinese medicine Bu-Shen-Jian-Pi-Fang (BSJPF) in the treatment of ccRCC based on network pharmacology. After obtaining the complete composition information for BSJPF from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, we analyzed its chemical composition and molecular targets and then established a pharmacological interaction network. Twenty-four significantly differentially expressed genes and nine pathways mainly related to tumor proliferation were identified and screened. Functional enrichment analysis indicated that the potential targets might be significantly involved in glycolysis and the HIF-1 signaling pathway. To further confirm the effect of BSJPF on ccRCC cell proliferation, a BALB/c xenograft mouse model was constructed. Potential targets involved in regulating glycolysis and the tumor immune microenvironment were evaluated using RT-qPCR. VEGF-A expression levels were markedly decreased, and heparin binding-EGF expression was increased in the BSJPF group. BSJPF also inhibited tumor proliferation by enhancing GLUT1- and LDHA-related glycolysis and the expression of the immune checkpoint molecules PD-L1 and CTLA-4, thereby altering the immune-rejection status of the tumor microenvironment. In summary, the present study demonstrated that the mechanism of BSJPF involves multiple targets and signaling pathways related to tumorigenesis and glycolysis metabolism in ccRCC. Our research provides a novel theoretical basis for the treatment of tumors with traditional Chinese medicine and new strategies for immunotherapy in ccRCC patients.

Background: CCL19 is a chemokine involved in cancer research due to its important role in the tumor microenvironment (TME) and clinical relevance in cancers. This study aimed to analyze transcription expression, genomic alteration, association with tumor immune microenvironment of CCL19 expression and its prediction value for prognosis and responses to immunotherapy for patients with cancers. Methods: RNA sequencing data and corresponding clinicopathological information of a total of large-scale cancer patients were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. Multiplex immunofluorescence (mIF) was implemented to identify differential infiltration of Treg, CD8+ T cells, and tumor-associated macrophages, while CCL19 immunohistochemistry was conducted on 182 breast cancer samples from a real-world cohort. Results: Based on large-scale multi-center survival analysis of cancer patients, we found the prognosis of patients with high CCL19 expression was prominently better than those with low CCL19 expression. For patients from multiple independent cohorts, suppressed CCL19 expression exerts significant progressive phenotype and apoptosis activity of cancers, especially in breast and ovarian cancer. Interestingly, anti-tumor immune cells, specifically the CD8+ T cells and macrophages, were clustered from TME by elevated CCL19 expression. Additionally, higher CCL19 levels reflected heightened immune activity and substantial heterogeneity. Conclusions: In conclusion, our findings support the notion that elevated CCL19 expression is linked to favorable outcomes and enhanced anti-tumor immunity, characterized by increased CD8+ T cells within the TME. This suggests the potential of CCL19 as a prognostic marker, predictive biomarker for immunotherapy, therapeutic target of cancers.

The escalating incidence of breast cancer (BC) in women underscores its grave health threat. Current molecular insights into BC's post-adjuvant therapy cure remain elusive, necessitating active treatment explorations. Immunotherapy, notably chemotherapy-induced immunogenic cell death (ICD), has emerged as a promising BC therapy. ICD harnesses chemotherapeutics to activate anti-tumor immunity via DAMPs, fostering long-term T-cell memory and primary BC cure. Besides chemotherapy drugs, Nanodrugs, traditional Chinese medicine (TCM) and ICIs also induce ICD, boosting immune response. ICIs, like PD-1/PD-L1 inhibitors, revolutionize cancer treatment but face limited success in cold tumors. Thus, ICD induction combined with ICIs is studied extensively for BC immunotherapy. This article reviews the mechanism of ICD related drugs in BC and provides reference for the research and development of BC treatment, in order to explore more effective clinical treatment of BC, we hope to explore more ICD inducers and make ICIs more effective vaccines. Graphical abstract

The tumor microenvironment (TME) performs a crucial function in the tumorigenesis and response to immunotherapies of clear cell renal cell carcinoma (ccRCC). However, a lack of recognized pre-clinical TME-based risk models poses a great challenge to investigating the risk factors correlated with prognosis and treatment responses for patients with ccRCC. Stromal and immune contexture were assessed to calculate the TMErisk score of a large sample of patients with ccRCC from public and real-world cohorts using machine-learning algorithms. Next, analyses for prognostic efficacy, correlations with clinicopathological features, functional enrichment, immune cell distributions, DNA variations, immune response, and heterogeneity were performed and validated. Clinical hub genes, including INAFM2, SRPX, DPYSL3, VSIG4, APLNR, FHL5, A2M, SLFN11, ADAMTS4, IFITM1, NOD2, CCR4, HLA-DQB2, and PLAUR, were identified and incorporated to develop the TMErisk signature. Patients in the TME^high risk group (category) exhibited a considerably grim prognosis, and the TMErisk model was shown to independently function as a risk indicator for the overall survival (OS) of ccRCC patients. Expression levels of immune checkpoint genes were substantially increased in TME^high risk group, while those of the human leukocyte antigen (HLA) family genes were prominently decreased. In addition, tumors in the TME^high group showed significantly high infiltration levels of tumor-infiltrated lymphocytes, including M2 macrophages, CD8⁺ T cells, B cells, and CD4⁺ T cells. In heterogeneity analysis, more frequent somatic mutations, including pro-tumorigenic BAP1 and PBRM1, were observed in the TME^high group. Importantly, 19.3% of patients receiving immunotherapies in the TME^high group achieved complete or partial response compared with those with immune tolerance in the TME^low group, suggesting that TMErisk prominently differentiates prognosis and responses to immunotherapy for patients with ccRCC. We first established the TMErisk score of ccRCC using machine-learning algorithms based on a large-scale population. The TMErisk score can be utilized as an innovative independent prognosis predictive marker with high sensitivity and accuracy. Our discovery also predicted the efficacy of immunotherapy in ccRCC patients, indicating the intimate link between tumor immune microenvironment and intratumoral heterogeneity.