Evaluating Surgical Outcomes Between Estrogen Receptor Positive Invasive Lobular and Invasive Ductal Carcinoma of the Breast-A Propensity Matched Analysis.

INTRODUCTION: Invasive lobular carcinoma (ILC) contributes significantly to the global cancer burden and is the most common of the histological "special types" of breast cancer. ILC has unique features setting it apart from the more common invasive ductal carcinoma (IDC). Despite differences, treatment algorithms do not consider histological differences. AIM: To determine the differences in treatment and outcomes of ILC relative to IDC in a strict case-matched cohort study at a tertiary referral, specialist, breast cancer center. METHODS: All Estrogen receptor positive (ER+) ILCs from 1999 to 2015 were matched for; age, tumor size, grade, PR/HER2 status, nodal stage and metastases with ER+ IDCs from the same period. Surgical and systemic treatments were assessed along with overall (OS) and disease-free survival (DFS). RESULTS: 762 cases in total were analyzed (1:1 matching; ILC:IDC). ILC cases were more often treated with mastectomy (37.5% vs. 28.6%, P .009) and those who received breast conserving surgery (BCS) more often had an incomplete resection (30.2% vs. 19.6%, P .01). IDC were more often treated with NACT (5.5% vs. 14.4%, P < .001). Mean DFS were similar between ILC and IDC; 148.3 vs. 141.4 months (P .112) but OS was significantly longer in the ILC group; 165.7 vs. 134 months (P .002). This trend was consistent among the subset of patients undergoing BCS. For ILC undergoing BCS, mean DFS was 129.8 vs. 128.3 months for IDC (P .418) and OS was 155.4 and 110.7 months respectively (P < .001). Incomplete resection at the time of index surgery did not alter the disease free or overall survival in either the ILC or IDC patients to a level that reached statistical significance. CONCLUSION: In this cohort study, the strict matching of ILC and IDCs for a number of prognostic indicators, demonstrates the impact of lobular histology with a clarity not previously observed. ILCs have comparable survival outcomes to patients with IDC but at the expense of more extensive index and revisional surgery. There is a need for awareness of these facts among surgeons and patients for optimal treatment prioritization and provision.

Selective CO2 Electroreduction to Multi-Carbon Products on Organic-Functionalized CuO Nanoparticles by Local Micro-Environment Modulation.

Surface functionalization of Cu-based catalysts has demonstrated promising potential for enhancing the electrochemical CO2 reduction reaction (CO2RR) toward multi-carbon (C2+) products, primarily by suppressing the parasitic hydrogen evolution reaction and facilitating a localized CO2/CO concentration at the electrode. Building upon this approach, we developed surface-functionalized catalysts with exceptional activity and selectivity for electrocatalytic CO2RR to C2+ in a neutral electrolyte. Employing CuO nanoparticles coated with hexaethynylbenzene organic molecules (HEB-CuO NPs), a remarkable C2+ Faradaic efficiency of nearly 90% was achieved at an unprecedented current density of 300 mA cm-2, and a high FE (> 80%) was maintained at a wide range of current densities (100-600 mA cm-2) in neutral environments using a flow cell. Furthermore, in a membrane electrode assembly (MEA) electrolyzer, 86.14% FEC2+ was achieved at a partial current density of 387.6 mA cm-2 while maintaining continuous operation for over 50 h at a current density of 200 mA cm-2. In-situ spectroscopy studies and molecular dynamics simulations reveal that reducing the coverage of coordinated K⋅H2O water increased the probability of intermediate reactants (CO) interacting with the surface, thereby promoting efficient C-C coupling and enhancing the yield of C2+ products. This advancement offers significant potential for optimizing local micro-environments for sustainable and highly efficient C2+ production.

Strategies for the development of stimuli-responsive small molecule prodrugs for cancer treatment.

Approved anticancer drugs typically face challenges due to their narrow therapeutic window, primarily because of high systemic toxicity and limited selectivity for tumors. Prodrugs are initially inactive drug molecules designed to undergo specific chemical modifications. These modifications render the drugs inactive until they encounter specific conditions or biomarkers in vivo, at which point they are converted into active drug molecules. This thoughtful design significantly improves the efficacy of anticancer drug delivery by enhancing tumor specificity and minimizing off-target effects. Recent advancements in prodrug design have focused on integrating these strategies with delivery systems like liposomes, micelles, and polymerosomes to further improve targeting and reduce side effects. This review outlines strategies for designing stimuli-responsive small molecule prodrugs focused on cancer treatment, emphasizing their chemical structures and the mechanisms controlling drug release. By providing a comprehensive overview, we aim to highlight the potential of these innovative approaches to revolutionize cancer therapy.

Integrated single-cell and bulk RNA sequencing revealed an epigenetic signature predicts prognosis and tumor microenvironment colorectal cancer heterogeneity.

BACKGROUND: Colorectal cancer (CRC) prognosis prediction is currently a major challenge. Epigenetic regulation has been widely reported for its role in cancer development. AIM: To construct a robust prognostic signature, we used developed and validated across datasets. METHODS: After constructing the signature, the prognostic value of the signature was evaluated in the TCGA cohort and six independent datasets (GSE17526, GSE17537, GSE33113, GSE37892, GSE39048 and GSE39582). The clinical, genomic and transcriptomic features related to the signature were identified. The correlations of the signature score with immune cell infiltration and cell-cell interactions were analyzed. The correlations between the signature score and the sensitivity to different drugs were also predicted. RESULTS: In the TCGA cohort, patients in the low-risk group according to the signature score had longer survival than those in the high-risk group, and this finding was validated in the validation datasets. The signature was a prognostic factor independent of age and sex and was correlated with stage and PD-1/PD-L1 expression. Area under the receiving operating characteristic curve was 0.72. Genomic association analyses revealed that samples from high-risk patients exhibited chromosomal instability. Transcriptomic analyses revealed that the signature score was significantly associated with multiple cellular pathways. Bulk RNA-seq and single-cell sequencing data revealed that the signature reflected differences in infiltrating immune cell-tumor cell interactions, especially for macrophages. The signature also predicted the putative drug sensitivity of CRC samples. CONCLUSION: The signature is a valuable biomarker for predicting CRC prognosis and reflects multiple features of CRC, especially macrophage infiltration in the microenvironment.

Tumor phagocytosis-driven STING activation invigorates antitumor immunity and reprograms the tumor micro-environment.

Immunogenic cell death (ICD) holds the potential for in situ tumor vaccination while concurrently eradicating tumors and stimulating adaptive immunity. Most ICD inducers, however, elicit insufficient immune responses due to negative feedback against ICD biomarkers, limited infiltration of antitumoral immune cells, and the immunosuppressive tumor micro-environment (TME). Recent findings highlight the pivotal roles of stimulators of interferon gene (STING) activation, particularly in stimulating antigen-presenting cells (APCs) and TME reprogramming, addressing ICD limitations. Herein, we introduced 'tumor phagocytosis-driven STING activation', which involves the activation of STING in APCs during the recognition of ICD-induced cancer cells. We developed a polypeptide-based nanocarrier encapsulating both doxorubicin (DOX) and diABZI STING agonist 3 (dSA3) to facilitate this hypothesis in vitro and in vivo. After systemic administration, nanoparticles predominantly accumulated in tumor tissue and significantly enhanced anticancer efficacy by activating tumor phagocytosis-driven STING activation in MC38 and TC1 tumor models. Immunological activation of APCs occurred within 12 h, subsequently leading to the activation of T cells within 7 days, observed in both the TME and spleen. Furthermore, surface modification of nanoparticles with cyclic RGD (cRGD) moieties, which actively target integrin αvß3, enhances tumor accumulation and eradication, thereby verifying the establishment of systemic immune memory. Collectively, this study proposes the concept of tumor phagocytosis-driven STING activation and its effectiveness in generating short-term and long-term immune responses.

The immunotherapy in gastrointestinal stromal tumors.

Using Tyrosine Kinase Inhibitors (TKIs) for gastrointestinal stromal tumors (GIST) has significantly reduced the risk of recurrence and prolonged survival. Immunotherapy has demonstrated efficacy in multiple solid tumors, but its effectiveness in GIST remains uncertain. Although early clinical studies indicate good tolerability of immunotherapy in patients, the efficacy is not as desired. Therefore, identifying the subset of GIST patients who benefit from immunotherapy and coordinating the relationship between immunotherapy and TKI treatment are crucial issues to be explored. In this review, we aims to provide a retrospective analysis of relevant literature and find that GIST patients exhibit a rich presence of tumor-infiltrating immune cells, which play critical roles in the immune surveillance and evasion processes of tumors. This review incorporates a selection of 48 articles published between 2002 and 2023, sourced from PubMed, EBSCO, and Google Scholar databases.

The cross-talk between the macro and micro-environment in precursor lesions of pancreatic cancer leads to new and promising circulating biomarkers.

Pancreatic cancer (PC) is a clinically challenging tumor to combat due to its advanced stage at diagnosis as well as its resistance to currently available therapies. The absence of early symptoms and known detectable biomarkers renders this disease incredibly difficult to detect/manage. Recent advances in the understanding of PC biology have highlighted the importance of cancer-immune cell interactions, not only in the tumor micro-environment but also in distant systemic sites, like the bone marrow, spleen and circulating immune cells, the so-called macro-environment. The response of the macro-environment is emerging as a determining factor in tumor development by contributing to the formation of an increasingly immunogenic micro-environment promoting tumor homeostasis and progression. We will summarize the key events associated with the feedback loop between the tumor immune micro-environment (TIME) and the tumor immune macroenvironment (TIMaE) in pancreatic precancerous lesions along with how it regulates disease development and progression. In addition, liquid biopsy biomarkers capable of diagnosing PC at an early stage of onset will also be discussed. A clearer understanding of the early crosstalk between micro-environment and macro-environment could contribute to identifying new molecular therapeutic targets and biomarkers, consequently improving early PC diagnosis and treatment.

Non-Coding RNA in Tumor Cells and Tumor-Associated Myeloid Cells-Function and Therapeutic Potential.

The RNA world is wide, and besides mRNA, there is a variety of other RNA types, such as non-coding (nc)RNAs, which harbor various intracellular regulatory functions. This review focuses on small interfering (si)RNA and micro (mi)RNA, which form a complex network regulating mRNA translation and, consequently, gene expression. In fact, these RNAs are critically involved in the function and phenotype of all cells in the human body, including malignant cells. In cancer, the two main targets for therapy are dysregulated cancer cells and dysfunctional immune cells. To exploit the potential of mi- or siRNA therapeutics in cancer therapy, a profound understanding of the regulatory mechanisms of RNAs and following targeted intervention is needed to re-program cancer cells and immune cell functions in vivo. The first part focuses on the function of less well-known RNAs, including siRNA and miRNA, and presents RNA-based technologies. In the second part, the therapeutic potential of these technologies in treating cancer is discussed, with particular attention on manipulating tumor-associated immune cells, especially tumor-associated myeloid cells.

Advances in the role of circulating tumor cell heterogeneity in metastatic small cell lung cancer.

Small cell lung cancer (SCLC), a highly aggressive malignancy, is rapidly at an extensive stage once diagnosed and is one of the leading causes of death from malignancy. In the past decade, the treatment of SCLC has largely remained unchanged, and chemotherapy remains the cornerstone of SCLC treatment. The therapeutic value of adding immune checkpoint inhibitors to chemotherapy for SCLC is low, and only a few SCLC patients have shown a response to immune checkpoint inhibitors. Circulating tumor cells (CTCs) are tumor cells shed from solid tumor masses into the peripheral circulation and are key to tumor metastasis. Single-cell sequencing has revealed that the genetic profiles of individual CTCs are highly heterogeneous and contribute to the poor outcome and prognosis of SCLC patients. Theoretically, phenotypic analysis of CTCs may be able to predict the diagnostic significance of new potential targets for metastatic tumors. In this paper, we will discuss in depth the heterogeneity of CTCs in SCLC and the value of CTCs for the diagnosis and prognosis of SCLC and as relevant tumor markers in metastatic SCLC.

Dihydroartemisinin remodels tumor micro-environment and improves cancer immunotherapy through inhibiting cyclin-dependent kinases.

Cancer immunotherapies are ineffective in nonresponding patients due to absence of immune responses. Here, we identified that dihydroartemisinin (DHA) induced immunogenic cell death (ICD) in hepatocellular carcinoma (HCC), proved by release or surface expose of damage-associated molecular patterns and in vivo protective vaccine activity. Mechanistically, DHA can inhibit cyclin-dependent kinases (CDKs), leading to a buildup of intracellular reactive oxygen species (ROS), which induces immunogenic cell death. In both Hepa1-6 and H22 tumor bearing mice, DHA exerted anti-tumor activity through increasing tumor-infiltrating CD8+ T cells with expression of activation makers (CD25 and CD69), secretion of intracellular cytokines (IFN-γ and TNF-α) and activated dendritic cells expressing MHCⅡ, CD80 and CD86. In hepa1-6 tumor bearing mice, DHA decreased immunosuppressive myeloid-derived suppressor cells. Furthermore, DHA enhanced the anti-PD-1 antibody and chimeric antigen receptor (CAR) T cell-mediated tumor suppression through recruitment and activation of endogenous CD8+ T cells. Overall, we demonstrated that by inhibiting CDKs, DHA can remodel tumor micro-environment to amplify anti-tumor immune responses in HCC. These findings provide a promising therapy option for HCC patients.

Identification of JUN gene and cellular microenvironment in response to PD-1 blockade treatment in lung cancer patients via single-cell RNA sequencing.

Exploring the molecular mechanisms of PD-1/PDL-1 blockade for non-small cell lung cancer (NSCLC) would facilitate understanding for tumor microenvironment (TME) and development of individualized medicine. To date, biomarkers of response to PD-1 blockade therapy were still limited. In this study, we hypothesize that cell type in the tumor microenvironment can influence the effect of PD-1 blockade immunotherapy through specific genes. Therefore, we re-analyze the single-cell RNA sequencing data and validation in tissue from lung adenocarcinoma patients. Dynamic changes of cellular subpopulation were observed after anti-PD-1 immunotherapy among TMEs between primary/metastasis or good/poor response patients. Non-exhausted CD8 T cells and dysregulated genes were observed in responsing patients from PD-1 blockade therapy. Among all changed genes, JUN, involved in PD-1 blockade immunotherapy pathway, and could be considered as a PD-1 responsing biomarker.

A Comprehensive Pan-Cancer Analysis of Cytochrome C Oxidase Assembly Factor 1 (COA1) Reveals Instrumental Role of Mitochondrial Protein Assembly in Cancer that Modulates Disease Progression and Prognostic Outcome.

Cytochrome c oxidase assembly factor 1 (COA1), a mitochondrial respiratory chain complex assembly factor protein of inner mitochondrial membrane (IMM), is involved in translating many mitochondrial components and assembling nuclear-encoded components within mitochondria. Given the lack of extensive research on COA1 in cancer, this study undertakes a comprehensive pan-cancer analysis of COA1, which is overexpressed across various cancer types, shedding light on its multifaceted role in tumorigenesis, prognosis, and tumor microenvironment (TME) modulation. Leveraging bioinformatics tools and public databases, we elucidated its potential as a diagnostic cancer biomarker as well as a target for novel anti-cancer therapeutics. Gene expression analysis using "TIMER2.0", "UALCAN" and "GEPIA2" platforms, supported by protein expression data, revealed a significant correlation between COA1 upregulation and poor prognosis in Kaplan-Meir analysis, underscoring its clinical relevance. Additionally, genetic mutation analysis of COA1 with the help of "cBioPortal" warrants further exploration into its functional significance. Moreover, our investigation of the tumor microenvironment unveiled the interplay of COA1 with fibroblast and T cell infiltration implicating the role of COA1 in the tumor immune microenvironment. Furthermore, COA1-related gene enrichment study in "GeneMANIA" and pathway cross-talk analysis with Gene Ontology (GO) gene sets established comprehensive clarifications about the molecular pathways and protein networks associated with COA1 deregulation. Overall, this study lays a sturdy foundation to support future research endeavors targeting COA1, unraveling the molecular mechanisms underlying COA1 deregulation, and exploring its therapeutic potential in cancer.

Immune micro-environment analysis and drug screening for ovarian endometriosis.

BACKGROUND: Patients of ovary endometriosis have an abnormal immune micro-environment, leading to endometrial tissue that from retrograde menstruation evade immune surveillance and subsequently develop into ectopic lesions. OBJECTIVE: This study aims to elucidate the crucial immune cells and molecular pathways that are associated with an aberrant immune micro-environment of endometriosis. METHOD: In this study, we identified differentially expressed genes between ovarian ectopic endometrial tissue (OVE) and eutopic endometrial tissue from patients with endometriosis (PE) and non-endometriosis patients (CON) by analyzing the mRNA sequencing data. Additionally, we used WGCNA(Weighted Gene Co-expression Network Analysis) to screen for key genes related to immune cell infiltration and compared the sub-types of infiltrating immune cells using CIBERSORT(cell-type identification by estimating relative subsets of RNA transcript). Subsequently, we conducted a single-cell analysis on the identified key genes. Furthermore, we analyzed potential drugs suitable for ovarian endometriosis treatment using pRRophertic. RESULTS: Seven key genes associated with immune cell infiltration were screened out. The expression of these genes in OVE was significantly lower than that in PE and CON. These key genes were mainly enriched in the NK cell-mediated cytotoxicity pathway, especially for CD16 + CD56dim NK. Moreover, NK cells infiltration in ovarian endometriosis was significantly reduced compared with PE and CON, while M2 macrophage shown the opposite. Results of the single-cell analysis showed that the expression of the seven key genes in NK cells and monocyte-macrophages in OVE was significantly lower than that in PE or CON. Additionally, we identified potential drugs suitable for ovarian endometriosis treatment. CONCLUSION: The decreased infiltration of NK cells and increased infiltration of M2 macrophages contribute to the evasion of immune surveillance against endometrial tissue, promoting the progression of OVE. Therefore, potential strategies for the treatment of OVE include increasing NK cell activation and decreasing M2 macrophage polarization.

Modelling the micro- and macro- environment of pancreatic cancer: from patients to pre-clinical models and back.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with very low survival rates. Over the past 50 years, improvements in PDAC survival have significantly lagged behind the progress made in other cancers. PDAC's dismal prognosis is due to typical late-stage diagnosis combined with lack of effective treatments and complex mechanisms of disease. We propose that improvements in survival are partly hindered by the current focus on largely modelling and targeting PDAC as one disease, despite it being heterogeneous. Implementing new disease-representative pre-clinical mouse models that capture this complexity could enable the development of transformative therapies. Specifically, these models should recapitulate human PDAC late-stage biology, heterogeneous genetics, extensive non-malignant stroma, and associated risk factors and comorbidities. In this Perspective, we focus on how pre-clinical mouse models could be improved to exemplify key features of PDAC micro- and macro- environments, which would drive clinically relevant patient stratification, tailored treatments and improved survival.

In situ/Operando Synchrotron Radiation Analytical Techniques for CO2/CO Reduction Reaction: From Atomic Scales to Mesoscales.

Electrocatalytic carbon dioxide/carbon monoxide reduction reaction (CO(2)RR) has emerged as a prospective and appealing strategy to realize carbon neutrality for manufacturing sustainable chemical products. Developing highly active electrocatalysts and stable devices has been demonstrated as effective approach to enhance the conversion efficiency of CO(2)RR. In order to rationally design electrocatalysts and devices, a comprehensive understanding of the intrinsic structure evolution within catalysts and micro-environment change around electrode interface, particularly under operation conditions, is indispensable. Synchrotron radiation has been recognized as a versatile characterization platform, garnering widespread attention owing to its high brightness, elevated flux, excellent directivity, strong polarization and exceptional stability. This review systematically introduces the applications of synchrotron radiation technologies classified by radiation sources with varying wavelengths in CO(2)RR. By virtue of in situ/operando synchrotron radiationanalytical techniques, we also summarize relevant dynamic evolution processes from electronic structure, atomic configuration, molecular adsorption, crystal lattice and devices, spanning scales from the angstrom to the micrometer. The merits and limitations of diverse synchrotron characterization techniques are summarized, and their applicable scenarios in CO(2)RR are further presented. On the basis of the state-of-the-art fourth-generation synchrotron facilities, a perspective for further deeper understanding of the CO(2)RR process using synchrotron radiation analytical techniques is proposed.

Comprehensive single-cell analysis reveals heterogeneity of fibroblast subpopulations in ovarian cancer tissue microenvironment.

Background: Ovarian cancer, as a highly malignant tumor, features the critical involvement of tumor-associated fibroblasts in the ovarian cancer tissue microenvironment. However, due to the apparent heterogeneity within fibroblast subpopulations, the specific functions of these subpopulations in the ovarian cancer tissue microenvironment remain insufficiently elucidated. Methods: In this study, we integrated single-cell sequencing data from 32 ovarian cancer samples derived from four distinct cohorts and 3226 bulk RNA-seq data from GEO and TCGA-OV cohorts. Utilizing computational frameworks such as Seurat, Monocle 2, Cellchat, and others, we analyzed the characteristics of the ovarian cancer tissue microenvironment, focusing particularly on fibroblast subpopulations and their differentiation trajectories. Employing the CIBERSORTX computational framework, we assessed various cellular components within the ovarian cancer tissue microenvironment and evaluated their associations with ovarian cancer prognosis. Additionally, we conducted Mendelian randomization analysis based on cis-eQTL to investigate causal relationships between gene expression and ovarian cancer. Results: Through integrative analysis, we identified 13 major cell types present in ovarian cancer tissues, including CD8+ T cells, malignant cells, and fibroblasts. Analysis of the tumor microenvironment (TME) cell proportions revealed a significant increase in the proportion of CD8+ T cells and CD4+ T cells in tumor tissues compared to normal tissues, while fibroblasts predominated in normal tissues. Further subgroup analysis of fibroblasts identified seven subgroups, with the MMP11+Fib subgroup showing the highest activity in the TGFß signaling pathway. Single-cell analysis suggested that oxidative phosphorylation could be a key pathway driving fibroblast differentiation, and the ATRNL1+KCN + Fib subgroup exhibited chromosomal copy number variations. Prognostic analysis using a large sample size indicated that high infiltration of MMP11+ fibroblasts was associated with poor prognosis in ovarian cancer. SMR analysis identified 132 fibroblast differentiation-related genes, which were linked to pathways such as platinum drug resistance. Conclusions: In the context of ovarian cancer, fibroblasts expressing MMP11 emerge as the primary drivers of the TGF-beta signaling pathway. Their presence correlates with an increased risk of adverse ovarian prognoses. Additionally, the genetic regulation governing the differentiation of fibroblasts associated with ovarian cancer correlates with the emergence of drug resistance.

Habitat-based radiomics analysis for evaluating immediate response in colorectal cancer lung metastases treated by radiofrequency ablation.

PURPOSE: To create radiomics signatures based on habitat to assess the instant response in lung metastases of colorectal cancer (CRC) after radiofrequency ablation (RFA). METHODS: Between August 2016 and June 2019, we retrospectively included 515 lung metastases in 233 CRC patients who received RFA (412 in the training group and 103 in the test group). Multivariable analysis was performed to identify independent risk factors for developing the clinical model. Tumor and ablation regions of interest (ROI) were split into three spatial habitats through K-means clustering and dilated with 5 mm and 10 mm thicknesses. Radiomics signatures of intratumor, peritumor, and habitat were developed using the features extracted from intraoperative CT data. The performance of these signatures was primarily evaluated using the area under the receiver operating characteristics curve (AUC) via the DeLong test, calibration curves through the Hosmer-Lemeshow test, and decision curve analysis. RESULTS: A total of 412 out of 515 metastases (80%) achieved complete response. Four clinical variables (cancer antigen 19-9, simultaneous systemic treatment, site of lung metastases, and electrode type) were utilized to construct the clinical model. The Habitat signature was combined with the Peri-5 signature, which achieved a higher AUC than the Peri-10 signature in the test set (0.825 vs. 0.816). The Habitat+Peri-5 signature notably surpassed the clinical and intratumor radiomics signatures (AUC: 0.870 in the test set; both, p < 0.05), displaying improved calibration and clinical practicality. CONCLUSIONS: The habitat-based radiomics signature can offer precise predictions and valuable assistance to physicians in developing personalized treatment strategies.

Complement factor H: a novel innate immune checkpoint in cancer immunotherapy.

The elimination of cancer cells critically depends on the immune system. However, cancers have evolved a variety of defense mechanisms to evade immune monitoring, leading to tumor progression. Complement factor H (CFH), predominately known for its function in inhibiting the alternative pathway of the complement system, has recently been identified as an important innate immunological checkpoint in cancer. CFH-mediated immunosuppression enhances tumor cells' ability to avoid immune recognition and produce an immunosuppressive tumor microenvironment. This review explores the molecular underpinnings, interactions with immune cells, clinical consequences, and therapeutic possibilities of CFH as an innate immune checkpoint in cancer control. The difficulties and opportunities of using CFH as a target in cancer immunotherapy are also explored.

Prediction of immunotherapy responsiveness in melanoma through single-cell sequencing-based characterization of the tumor immune microenvironment.

Immune checkpoint inhibitors (ICB) therapy have emerged as effective treatments for melanomas. However, the response of melanoma patients to ICB has been highly heterogenous. Here, by analyzing integrated scRNA-seq datasets from melanoma patients, we revealed significant differences in the TiME composition between ICB-resistant and responsive tissues, with resistant or responsive tissues characterized by an abundance of myeloid cells and CD8+ T cells or CD4+ T cell predominance, respectively. Among CD4+ T cells, CD4+ CXCL13+ Tfh-like cells were associated with an immunosuppressive phenotype linked to immune escape-related genes and negative regulation of T cell activation. We also develop an immunotherapy response prediction model based on the composition of the immune compartment. Our predictive model was validated using CIBERSORTx on bulk RNA-seq datasets from melanoma patients pre- and post-ICB treatment and showed a better performance than other existing models. Our study presents an effective immunotherapy response prediction model with potential for further translation, as well as underscores the critical role of the TiME in influencing the response of melanomas to immunotherapy.