This study aimed to identify the key cell types and their interactions in gynecological oncology of breast cancer, cervical cancer, and ovarian cancer. Single-cell RNA sequencing was performed on tumor samples of gynecological oncology from the GEO database. Cell types were identified using SingleR and cell composition was analyzed to understand the tumor microenvironment (TME). CellChat was used to analyze cell interactions, and pseudotemporal analysis was conducted on cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) to understand their differentiation status. Four CAF subtypes were identified: iCAF, myCAF, proCAF, and matCAF. The iCAF subpopulation secreted COL1A1 and promoted tumor cell migration, while myCAF was involved in angiogenesis. The matCAF subpopulation was present throughout tumor development. TAMs were found to promote angiogenesis through the VEGFA_VEGFR2 signaling pathway. CAFs and TAMs play pivotal roles in tumor progression through their interactions and signaling pathways.

Acute myeloid leukemia (AML), the most prevalent acute leukemia in adults, is characterized by its heterogeneity, which contributes to a poor prognosis and high recurrence rate. Recently, a unique form of cell death, called disulfidptosis, has been identified, which could transforming our understanding of and strategy for cancer treatment. Consequently, further inquiry is necessary to explore the possible link between disulfidptosis and AML. To facilitate this analysis, the researchers obtained single-cell RNA sequencing (scRNA-seq) data from AML patients using the Gene Expression Omnibus (GEO) database. By applying the Cox proportional hazards model and least absolute shrinkage and selection operator (LASSO) regression analysis, we created a signature of disulfidptosis-related long non-coding RNAs (DRLs). This predictive model was established based on six specific DRLs (AC005076.1, AP002807.1, HDAC4-AS1, L3MBTL4-AS1, LINC01694, and THAP9-AS1). The utility of this model in forecasting the prognosis of AML patients was corroborated by the receiver operating characteristic (ROC) curve. Moreover, significant variations in the biological functions and signaling pathways were discovered by gene ontology (GO) and Gene Set Enrichment Analysis (GSEA). To further investigate the relationship between immune infiltration, the study assessed variations in immune checkpoint expression and immune cell subset infiltration. Additionally, we used real-time quantitative PCR (RT-qPCR) to detect lncRNA expression in AML and healthy control to substantiate our analysis results. In conclusion, the results of this study may help discover novel therapeutic targets and prognostic biomarkers for AML, paving the way for customized precision chemotherapy.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer, with local immunity playing a key role in regulating outcome. Nonresolving inflammation has been suggested to drive cancer growth; however, a fundamental understanding of the tumor immune microenvironment in cSCC is still lacking. In this study, we demonstrate tissue-associated tumor eosinophilia in both human and murine cSCC and show that eosinophils promote epithelial hyperplasia and tumor outgrowth. The skin eosinophils display tissue adaptation and dynamically alter their transcriptome according to the microenvironment. Furthermore, we show that the skin bioactive lipidome is significantly altered during inflammation and in cSCC and that this is regulated by eosinophils. Inflamed skin and cSCC tissue are dominated by lipid mediators synthesized by lipoxygenase enzymes, and our results suggest that eosinophils influence the balance between proinflammatory and proresolving lipid mediators. We demonstrate that lipid mediators can regulate epithelial cell expansion, with PCTR1 reducing inflammation-driven growth of tumor cells and eosinophil-driven eoxin C4 blocking this effect. Together, these findings highlight that eosinophils and specific bioactive lipid mediators play important roles in skin biology and carcinogenesis and point to potential previously unreported strategies for treatment of inflammatory disorders and epithelial malignancies.

Urine samples are non-invasive approaches to study potential circulating biomarkers from the host organism. Specific proteins cross the bloodstream through the intestinal barrier and may also derive from gut microbiota. In this study, we aimed to evaluate the predictive role of the host and bacterial urine extracellular vesicle (EV) proteomes in patients with non-small cell lung cancer (NSCLC) treated with anti-PD1 immunotherapy.

We analyzed the urine EV proteome of 33 advanced-stage NSCLC patients treated with anti-PD1 immunotherapy with LC-MS/MS, stratifying patients according to long (>6 months) and short (≤6 months) progression-free survival (PFS). Gut microbial communities on a subcohort of 23 patients were also analyzed with shotgun metagenomics. Internal validation was performed using the Random Forest (RF) machine learning (ML) algorithm. RF was validated with a non-linear Bayesian ML model. Gene enrichment, and pathway analysis of host urine proteins were analyzed using the Reactome and Gene Ontology databases.

We identified human (n=3513), bacterial (n=2647), fungal (n=19), and viral (n=4) proteins. 186 human proteins showed differential abundance (p<0.05) according to PFS groups, 101 being significantly more abundant in patients with short PFS and n=85 in patients with long PFS. We found several pathways that were significantly enriched in patients with short PFS (vs long PFS). Multivariate Cox regression showed that human urine proteins MPP5, IGKV6-21, NT5E, and KRT27 were strongly associated with long PFS, and LMAN2, NUTF2, NID1, TNC, IGF1, BCR, GPHN, and PPBP showed the strongest association with short PFS. We revealed that an increased bacterial/host protein ratio in the urine is more frequent in patients with long PFS. Increased abundance of E. coli and E. faecalis proteins in the urine positively correlates with their gut metagenomic abundance. RF ML model supported the reliability in predicting PFS for critical human urine proteins (AUC=0.89), accuracy (95%) and Bacterial proteins (AUC=0.74).

To our knowledge, this is the first study to depict the predictive role of the host and bacterial urine proteome in anti-PD1-treated advanced NSCLC.

Tumor growth and spread are sustained by the tumor microenvironment. Inflammatory cells and pathways have a fundamental role in the tumor microenvironment, driving or conditioning the functional activation of other leukocyte subsets and favoring evasion of anti-tumor immunity. One of the inflammatory pathways contributing to cancer-related inflammation is the complement system. Complement has long been considered an immune mechanism associated with immunosurveillance. More recently it emerged as a tumor promoting pathway, due to direct effects on cancer cells or indirect effects via immunosuppression driven by myeloid cells. The role of complement in cancer is complex and ambiguous, and depends on the tumor type and stage, as well as other factors including oncogenic drivers, leukocyte infiltration, interactions with other tumor microenvironment components or tumor cells. Other factors of complexity include the source of complement molecules, its canonical or non-canonical extracellular functions, its potential intracellular activation, and the interaction with other systems, such as the coagulation or the microbiome. Preclinical studies generally demonstrate the involvement of complement activation in smouldering inflammation in cancer and promotion of an immunosuppressive environment. These studies paved the way for clinical trials aimed at enhancing the potential of immunotherapy, in particular by targeting complement-dependent myeloid-sustained immunosuppression. However, the complex role of complement in cancer and the multiplicity of complement players may represent stumbling blocks and account for failures of clinical trials, and suggest that further studies are required to identify patient subsets who may benefit from specific complement molecule targeting in combination with conventional therapies or immunotherapy. Here, we will discuss the anti- or pro-tumor role of complement activation in cancer, focusing on the interactions of complement with immune cells within the tumor microenvironment, in particular the myeloid compartment. Furthermore, we will examine the potential of complement targeting in cancer treatment, particularly in the context of macrophage reprogramming.

Advanced hepatocellular carcinoma (HCC) presents a strongly immunosuppressive tumor microenvironment, which enables tumor cells to evade immune cell attacks and hinder effective drug killing, thereby hindering the achievement of the desired therapeutic effect. In response, a novel nanoplatform- AuHNR@γ-Fe2O3@Lenvatinib@β-Glucan (AFLG) with surface modified β-1,3-glucan is developed, which exhibits potent immunostimulatory effect and the capability of repolarizing macrophages, to counteract the immunosuppressive conditions present in the tumor microenvironment. Leveraging the hollow structure of gold nanorods, Lenvatinib is efficiently loaded, a first-line targeted drug for HCC, which effectively inhibits tumor angiogenesis. Additionally, through atomic layer deposition, γ-Fe2O3 is generated on the hollow gold nanorod surface, endowing it with chemodynamic therapy and magnetic resonance T2-weighted imaging capabilities while excellently maintaining the gold nanorod's superior photothermal therapy and photoacoustic imaging properties under 1064 nm excitation. These AFLG NPs feature dual-modal imaging and quadruple-modal synergistic therapy capabilities, along with their powerful potential in remodeling the immunosuppressive tumor microenvironment, offering an encouraging novel approach for the treatment of hepatocellular carcinoma.

We report a case of complete remission in anaplastic oligodendroglioma following adoptive cell therapy (ACT) with autologous Wilms tumor 1 (WT-1)-specific CD8+ T cells. A 40-year-old woman referred to our hospital for adjuvant chemotherapy after recurrent anaplastic oligodendroglioma initially presented with a left frontal tumor, diagnosed through seizure onset, and subtotal resection confirmed oligodendroglioma (WHO grade 2). Radiation therapy treated the residual tumor, achieving partial remission until recurrence 2.5 years later when malignant transformation to anaplastic oligodendroglioma (WHO grade 3) occurred following a second craniotomy. After three cycles of procarbazine, lomustine, and vincristine chemotherapy, the residual tumor stabilized for 3 years. However, follow-up MRI identified a new enhancing lesion, prompting a third craniotomy. Recurrent anaplastic oligodendroglioma was confirmed, and adjuvant proton beam therapy and temozolomide chemotherapy were initiated. Two years later, another enhancing lesion appeared on the adjacent medial frontal lobe. Following multidisciplinary review, we introduced WT-1-specific ACT. Although transient swelling was observed 1 month post-therapy, the tumor demonstrated a response within 3-9 months. Continued regression led to complete remission-confirmed via MRI at the 15-month follow-up and sustained for 4.7 years. The patient's peripheral blood monocyte profiles and immune-associated cytokine analysis indicated T-cell activation following WT-1 sensitization.

Fibroinflammation refers to the highly integrated fibrogenic and inflammatory responses mediated by the concerted function of fibroblasts and innate immune cells in response to tissue perturbation. This process underlies the desmoplastic remodelling of the tumour microenvironment and thus plays an important role in tumour initiation, growth and metastasis. More specifically, fibroinflammation alters the biochemical and biomechanical signalling in malignant cells to promote their proliferation and survival and further supports an immunosuppressive microenvironment by polarizing the immune status of tumours. Additionally, the presence of fibroinflammation is often associated with therapeutic resistance. As such, there is increasing interest in targeting this process to normalize the tumour microenvironment and thus enhance the treatment of solid tumours. Herein, we review advances made in unravelling the complexity of cancer-associated fibroinflammation that can inform the rational design of therapies targeting this.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world, mainly because of its powerful pro-connective tissue proliferation matrix and immunosuppressive tumor microenvironment (TME), which promote tumor progression and metastasis. In addition, the extracellular matrix leads to vascular collapse, increased interstitial fluid pressure, and obstruction of lymphatic return, thereby hindering effective drug delivery, deep penetration, and immune cell infiltration. Therefore, reshaping the TME to enhance tumor perfusion, increase deep drug penetration, and reverse immune suppression has become a key therapeutic strategy. Traditional therapies for PDAC, including surgery, radiation, and chemotherapy, face significant limitations. Surgery is challenging due to tumor location and growth, while chemotherapy and radiation are hindered by the dense extracellular matrix and immunosuppressive TME. In recent years, the advancement of nanotechnology has provided new opportunities to improve drug efficacy. Nanoscale drug delivery systems (NDDSs) provide several advantages, including improved drug stability in vivo, enhanced tumor penetration, and reduced systemic toxicity. However, the clinical translation of nanotechnology in PDAC therapy faces several challenges. These include the need for precise targeting and control over drug release, potential immune responses to the nanocarriers, and the scalability and cost-effectiveness of production. This article provides an overview of the latest nanobased methods for achieving better therapeutic outcomes and overcoming drug resistance. We pay special attention to TME-targeted therapy in the context of PDAC, discuss the advantages and limitations of current strategies, and emphasize promising new developments. By emphasizing the enormous potential of NDDSs in improving the treatment outcomes of patients with PDAC, while critically discussing the limitations of traditional therapies and the challenges faced by nanotechnology in achieving clinical breakthroughs, our review paves the way for future research in this rapidly developing field.

Lung adenocarcinoma (LUAD) is responsible for majority cases of lung cancer and considered to be the primary cause of cancer-related mortality. The imbalance of cellular proliferation and apoptosis is critically implicated in the pathogenesis and progression of LUAD. Sphingomyelin, a vital lipid component, is integral to the regulation of tumor cell growth and apoptosis, and has garnered significant attention as a target in novel anticancer therapies. The pivotal molecules involved in sphingomyelin metabolism are crucial in modulating tumor cell behavior, thereby influencing clinical outcomes.

A comprehensive consensus clustering analysis was conducted by collecting clinical LUAD figures from the TCGA and GEO databases. By employing Cox regression and Lasso regression analysis, a prognostic model for LUAD patients was established by identifying seven sphingolipid-related genes (SRGs), and validated in the GEO database. The study also delved into the clinical relevance, functional capabilities, and immune implications of prognostic signals associated with sphingolipid metabolism. Finally, experiments conducted in vitro confirmed the imbalance of sphingolipid-associated genes in LUAD.

Using the prognostic model, lung adenocarcinoma (LUAD) patients can be divided into high-risk and low-risk groups. Meanwhile, we can observe marked disparities in survival times among these groups. Additionally, the model demonstrates high predictive accuracy in external validation cohorts. Research on the immune microenvironment and immunotherapy points to this risk stratification as a useful reference for immunotherapeutic strategies in LUAD. Finally, our hypothesis was corroborated through in vitro experiments.

This study demonstrates that sphingolipid-related gene prognostic characteristics correlate with tumor progression and recurrence, long-term prognosis, and immune infiltration in LUAD patients. The outcomes of our study could help shape innovative strategies for early intervention and prognosis prediction in lung adenocarcinoma.

T cells play diverse roles in cancer immunology, acting as tumor suppressors, cytotoxic effectors, enhancers of cytotoxic T lymphocyte responses and immune suppressors; providing memory and surveillance; modulating the tumor microenvironment (TME); or activating innate immune cells. However, cancer cells can disrupt T cell function, leading to T cell exhaustion and a weakened immune response against the tumor. The expression of exhausted T cell (Tex) markers plays a pivotal role in shaping the immune landscape of multiple cancers. Our aim was to systematically investigate the role of known T cell exhaustion (Tex) markers across multiple cancers while exploring their molecular interactions, mutation profiles, and potential implications for immunotherapy. The mRNA expression profile of six Tex markers, LAG-3, PDCD1, TIGIT, HAVCR2, CXCL13, and LAYN was investigated in pan-cancer. Utilizing data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), The Cancer Proteome Atlas (TCPA), and other repositories, we characterized the differential expression of the Tex markers, their association with the patients' survival outcome, and their mutation profile in multiple cancers. Additionally, we analyzed the effects on cancer-related pathways and immune infiltration within the TME, offering valuable insights into mechanisms of cancer immune evasion and progression. Finally, the correlation between their expression and sensitivity to multiple anti-cancer drugs was investigated extensively. Differential expression of all six markers was significantly associated with KIRC and poor prognosis in several cancers. They also played a potential activating role in apoptosis, EMT, and hormone ER pathways, as well as a potential inhibitory role in the DNA damage response and RTK oncogenic pathways. Infiltration of different immune cells was also found to be associated with the expression of the Tex-related genes in most cancer types. These findings underline that the reviving of exhausted T cells can be used to enhance the efficacy of immunotherapy in cancer patients.

Although inflammation has been widely associated with cancer development, how it affects the outcomes of immunotherapy and chemotherapy remains incompletely understood. Here, we show that CKLF-like MARVEL transmembrane domain-containing member 4 (CMTM4) is highly expressed in multiple human and murine cancer types including Lewis lung carcinoma, triple-negative mammary cancer and melanoma. In lung carcinoma, loss of CMTM4 significantly reduces tumor growth and impairs NF-κB, mTOR, and PI3K/Akt pathway activation. Furthermore, we demonstrate that CMTM4 can regulate epidermal growth factor (EGF) signaling post-translationally by promoting EGFR recycling and preventing its Rab-dependent degradation. Consequently, CMTM4 knockout sensitizes human lung tumor cells to EGFR inhibitors. In addition, CMTM4 knockout tumors stimulated with EGF show a decreased ability to produce inflammatory cytokines including granulocyte colony-stimulating factor (G-CSF), leading to decreased recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and therefore establishing a less suppressive tumor immune environment in both lung and mammary cancers. We also present evidence indicating that CMTM4-targeting siRNA-loaded liposomes reduce lung tumor growth in vivo and prolong animal survival. Knockout of CMTM4 enhances immune checkpoint blockade or chemotherapy to further reduce lung tumor growth. These data suggest that CMTM4 represents a novel target for the inhibition of tumor inflammation, and improvement of the immune response and tumor drug sensitivity.

Immune checkpoint inhibitors (ICIs) have ushered in a new era of therapies and play a significant role in the clinical treatment of a variety of tumors. However, immune resistance has increasingly created a bottleneck in treatment, making the question of how to overcome drug resistance an urgent issue to address. In this article, the mechanism of drug resistance is briefly described with a focus on how radiotherapy (RT) acts on the immune system to reverse immunotherapy failure. Combinations of existing treatment modalities need to be optimized to overcome resistance problems. Research has shown that some RT modalities reverse immune resistance or enhance efficacy when used in combination, which shows some value for immune resistance and is worthy of in-depth research.

In this review, we searched the literature published from 2000 to 2023 surrounding immunotherapy, RT and cancer.

Based on the immune effects and immunosuppressive effects induced by RT, this review examined the preclinical rationales of RT and its clinical results. The findings indicate that RT might provide a novel regimen for patients with locally advanced tumors, especially oligometastatic tumors.

Salvage therapy with RT after immunotherapy resistance is the focus of current research. Other strategies, such as multidrug combination therapies, have made preliminary progress in preclinical experiments. Further research on the roles of different RT doses, fractionation regimens, and other treatment sequences in salvage therapy need to be conducted in the future. The optimal site and timing of low-dose radiotherapy are also undetermined, and prospective studies are need to determine the best regimen for optimizing patient treatment.

Macrophages, as the predominant phagocytes, play an essential role in pathogens defense and tissue homeostasis maintenance. In the context of cancer, tumor-associated macrophages (TAMs) have evolved into cunning actors involved in angiogenesis, cancer cell proliferation and metastasis, as well as the construction of immunosuppressive microenvironment. Once properly activated, macrophages can kill tumor cells directly through phagocytosis or attack tumor cells indirectly by stimulating innate and adaptive immunity. Thus, the prospect of targeting TAMs has sparked significant interest and emerged as a promising strategy in immunotherapy. In this review, we summarize the diverse roles and underlying mechanisms of TAMs in cancer development and immunity and highlight the TAM-based therapeutic strategies such as inhibiting macrophage recruitment, inhibiting the differentiation reprogramming of TAMs, blocking phagocytotic checkpoints, inducing trained macrophages, as well as the potential of engineered CAR-armed macrophages in cancer therapy.

Non-small cell lung cancer (NSCLC), the most prevalent form of lung cancer, remains a leading cause of cancer-related mortality worldwide, particularly among elderly individuals. The phenomenon of immunosenescence, characterized by the progressive decline in immune cell functionality with aging, plays a pivotal role in NSCLC progression and contributes to the diminished efficacy of therapeutic interventions in older patients. Immunosenescence manifests through impaired immune surveillance, reduced cytotoxic responses, and increased chronic inflammation, collectively fostering a pro-tumorigenic microenvironment. This review provides a comprehensive analysis of the molecular, cellular, and genetic mechanisms of immunosenescence and its impact on immune surveillance and the tumor microenvironment (TME) in NSCLC. We explore how aging affects various immune cells, including T cells, B cells, NK cells, and macrophages, and how these changes compromise the immune system's ability to detect and eliminate tumor cells. Furthermore, we address the challenges posed by immunosenescence to current therapeutic strategies, particularly immunotherapy, which faces significant hurdles in elderly patients due to immune dysfunction. The review highlights emerging technologies, such as single-cell sequencing and CRISPR-Cas9, which offer new insights into immunosenescence and its potential as a therapeutic target. Finally, we outline future research directions, including strategies for rejuvenating the aging immune system and optimizing immunotherapy for older NSCLC patients, with the goal of improving treatment efficacy and survival outcomes. These efforts hold promise for the development of more effective, personalized therapies for elderly patients with NSCLC.

As an endogenous gas signaling molecule, hydrogen sulfide (H2S) has been proved to have a variety of biological activities. Studies have shown that in some disease state H2S concentration in the body is lower than normal state. Based on these findings, exogenous H2S supplementation is expected to be an effective treatment for many diseases. In recent years, a lot of H2S-releasing substances, namely H2S donors, have emerged as H2S sources. Specifically, various H2S donors also could be connected to drugs or compounds to form H2S donor conjugates. Many studies have found that H2S donor conjugates can not only retain the activity of the parent drug, but also reduce the adverse effects of the parent drug, this makes H2S donor conjugates to be a new kind of drug candidates. In this article, H2S donor conjugates will be reviewed and classified according to different diseases, such as inflammation, cardiovascular and cerebrovascular diseases, diseases of central nervous system and cancer. This review aims to provide an idea for researchers for further study of H2S and H2S donor conjugates.

It is worthwhile to establish a prognostic prediction model based on microenvironment cells (MCs) infiltration and explore new treatment strategies for triple-negative breast cancer (TNBC).

The xCell algorithm was used to quantify the cellular components of the TNBC microenvironment based on bulk RNA sequencing (bulk RNA-seq) data. The MCs index (MCI) was constructed using the least absolute shrinkage and selection operator Cox (LASSO-Cox) regression analysis. Single-cell RNA sequencing (scRNA-seq), spatially resolved transcriptomics (SRT), and multiplex immunofluorescence (mIF) staining analyses verified MCI. The mechanism of action of the MCI was investigated in tumor-bearing mice.

MCI consists of the six types of MCs, which can precisely predict the prognosis of the TNBC patients. scRNA-seq, SRT, and mIF analyses verified the existence and proportions of these cells. Furthermore, combined with the spatial distribution characteristics of the six types of MCs, an MCI-enhanced (MCI-e) model was constructed, which could predict the prognosis of the TNBC patients more accurately. More importantly, inhibition of the insulin signaling pathway activated in the cancer cells of the MCIhigh the TNBC patients significantly prolonged the survival time of tumor-bearing mice.

Overall, our results demonstrate that MCs infiltration can be exploited as a novel indicator for the prognosis and therapeutic regimen selection of the TNBC patients.

Despite remarkable progress in basic oncology, practical results remain unsatisfactory. This discrepancy is partly due to the exclusive focus on processes within the cancer cell, which results in a lack of recognition of cancer as a systemic disease. It is evident that a wise balance is needed between two alternative methodological approaches: reductionism, which would break down complex phenomena into smaller units to be studied separately, and holism, which emphasizes the study of complex systems as integrated wholes. A consistent holistic approach has so far led to the notion of cancer as a special organ, stimulating debate about its function and evolutionary significance. This article discusses the role of cancer as a mechanism of purifying selection of the gene pool, the correlation between hereditary and sporadic cancer, the cancer interactome, and the role of metastasis in a lethal outcome. It is also proposed that neutralizing the cancer interactome may be a novel treatment strategy.

This study aims to conduct a bibliometric analysis, employing visualization tools to examine literature pertaining to tumor immune evasion related to anti-CTLA-4 and anti-PD-1/PD-L1 therapy from 1999 to 2022. A special emphasis is placed on the interplay between tumor microenvironment, signaling pathways, immune cells and immune evasion, with data sourced from the Web of Science core collection (WoSCC). Advanced tools, including VOSviewer, Citespace, and Scimago Graphica, were utilized to analyze various parameters, such as co-authorship/co-citation patterns, regional contributions, journal preferences, keyword co-occurrences, and significant citation bursts. Out of 4778 publications reviewed, there was a marked increase in research focusing on immune evasion, with bladder cancer being notably prominent. Geographically, China, the USA, and Japan were the leading contributors. Prestigious institutions like MD Anderson Cancer Center, Harvard Medical School, Fudan University, and Sun Yat Sen University emerged as major players. Renowned journals in this domain included Frontiers in Immunology, Cancers, and Frontiers in Oncology. Ehen LP and Wang W were identified as prolific authors on this topic, while Topalian SL stood out as one of the most cited. Research current situation is notably pivoting toward challenges like immunotherapy resistance and the intricate signaling pathways driving drug resistance. This bibliometric study seeks to provide a comprehensive overview of past and current research trends, emphasizing the potential role of tumor microenvironment, signaling pathways and immune cells in the context of immune checkpoint inhibitors (ICIs) and tumor immune evasion.

Unresolved chronic inflammation, a hallmark of cancer, promotes tumor growth and metastasis in various cancer types. In contrast to blocking inflammation, stimulation of resolution of inflammation is an entirely novel approach to "resolve" inflammation. Resolution of inflammation mechanisms in cancer includes clearance of tumor debris, counter-regulation of pro-inflammatory eicosanoids and cytokines, and suppression of leukocyte infiltration. Conventional cytotoxic chemotherapy, radiation, anti-angiogenic therapy, and immune checkpoint inhibitors directly or indirectly can lead to the generation of pro-tumorigenic cellular debris. Over the past two decades, a potential paradigm shift has emerged in the inflammation field with the discovery of specialized pro-resolving mediators (SPMs), including resolvins, lipoxins, maresins, and protectins. SPMs are structurally distinct families of mediators grouped together by their pro-resolving "debris-clearing" functions. "Pro-resolving" therapies are in clinical development for various inflammation-driven diseases, including cancer. SPMs, as novel cancer therapeutics, have tremendous potential to enhance current cancer therapy. The mechanisms of SPMs as anti-cancer therapeutics are under active investigation by various laboratories worldwide. Here, we explore the current appreciation of the SPMs as innovative potential treatments designed to harness the unique anti-cancer activity of SPMs.

Cell division cycle 6 (CDC6) is essential for the initiation of DNA replication in eukaryotic cells and contributes to the development of various human tumors. Polycystic ovarian syndrome (PCOS) is a reproductive endocrine disease in women of childbearing age, with a significant risk of endometrial cancer (EC). However, the role of CDC6 in the progression of PCOS to EC is unclear. Therefore, we examined CDC6 expression in patients with PCOS and EC. We evaluated the relationship between CDC6 expression and its prognostic value, potential biological functions, and immune infiltrates in patients with EC. In vitro analyses were performed to investigate the effects of CDC6 knockdown on EC proliferation, migration, invasion, and apoptosis. CDC6 expression was significantly upregulated in patients with PCOS and EC. Moreover, this protein caused EC by promoting the aberrant infiltration of macrophages into the immune microenvironment in patients with PCOS. A functional enrichment analysis revealed that CDC6 exerted its pro-cancer and pro-immune cell infiltration functions via the PI3K-AKT pathway. Moreover, it promoted EC proliferation, migration, and invasion but inhibited apoptosis. This protein significantly reduced EC survival when mutated. These findings demonstrate that CDC6 regulates the progression of PCOS to EC and promotes immune infiltration.

Dermatomyositis (DM) is an inflammatory muscle disease that increases the risk of cancer, although the precise connection is not fully understood. The aim of this study was to investigate the mechanisms linking DM to cancer and identify potential therapeutic targets.

We conducted differential gene expression analysis on the GSE128470 dataset and employed WGCNA to pinpoint key genes related to DM. Central genes were identified with the LASSO and SVM-RFE methods. The expression levels and diagnostic relevance of these genes were confirmed via the GSE1551 dataset. Immune cell infiltration was analyzed in relation to central genes, and RT‒qPCR was utilized to evaluate the expression of key genes across various cancers.

In total, differentially expressed genes (DEGs), involved mainly in innate immunity, cytokine responses, and autoimmune diseases, were identified. In the WGCNA, 399 significant genes related to DM were identified, with central genes including MIF, C1QA, and CDKN1A. Immune infiltration analysis revealed diverse immune cell populations in DM patients, with significant correlations between central genes and these immune cells. MIF levels were notably elevated in various tumors and correlated with the prognosis of specific cancers. Furthermore, MIF was negatively associated with most immune cells but positively correlated with CD4+ Th1 cells, NKT cells, and MDSCs. Factors such as immune regulatory elements, TMB, and MSI indicated that MIF may affect immunotherapy outcomes. The increased expression of MIF mRNA was confirmed via RT‒qPCR.

The findings demonstrate that MIF, C1QA, and CDKN1A are differentially expressed in DM patients, with MIF showing significant alterations in DM patients with cancer. MIF may serve as a crucial prognostic biomarker and therapeutic target for various cancers, playing a pivotal role in linking DM to cancer through the modulation of CD4+ Th1 cells, NKT cells, and MDSCs.

As tumor-associated macrophages (TAM) exercise a plethora of protumor and immune evasive functions, novel strategies targeting TAMs to inhibit tumor progression have emerged within the current arena of cancer immunotherapy. Activation of the mannose receptor 1 (CD206) is a recent approach that recognizes immunosuppressive CD206high M2-like TAMs as a drug target. Ligation of CD206 both induces reprogramming of CD206high TAMs toward a proinflammatory phenotype and selectively triggers apoptosis in these cells. CD206-activating therapeutics are currently limited to the linear, 10mer peptide RP-182, 1, which is not a drug candidate. In this study, we sought to identify a better suitable candidate for future clinical development by synthesizing and evaluating a series of RP-182 analogs. Surprisingly, fatty acid derivative 1a [RP-182-PEG3-K(palmitic acid)] not only showed improved stability but also increased affinity to the CD206 receptor through enhanced interaction with a hydrophobic binding motif of CD206. Peptide 1a showed superior in vitro activity in cell-based assays of macrophage activation which was restricted to CD206high M2-polarized macrophages. Improvement in responses was disproportionally skewed toward improved induction of phagocytosis including cancer cell phagocytosis. Peptide 1a reprogrammed the immune landscape in genetically engineered murine KPC pancreatic tumors toward increased innate immune surveillance and improved tumor control and effectively suppressed tumor growth of murine B16 melanoma allografts.

Colorectal liver metastases grow following different histologic growth patterns (HGPs), classified as desmoplastic and nondesmoplastic (dHGP, non-dHGP), being the latter associated with worst prognosis. This study aimed to investigate the tumor microenvironment (TME) between HGPs supporting different survival. Multiplexed immunohistochemical staining was performed with the Opal7 system in a 100-patients cohort to evaluate the tumor-liver interface with three different cell panels: lymphoid, myeloid, and carcinoma-associated fibroblasts. Differences between HGPs were assessed by Mann-Whitney U test with Pratt correction and Holm-Bonferroni multitest adjustment. Cytotoxic T-cells were more abundant in tumoral areas of dHGP, while non-dHGP had higher macrophages infiltration, Th2, CD163+, and Calprotectin+ cells as well as higher pSMAD2 expression. Regarding carcinoma-associated fibroblasts, several subsets expressing COL1A1 were enriched in dHGP, while αSMAlow_single cells were present at higher densities in non-dHGP. Interestingly, Calprotectin+ cells confer better prognoses in non-dHGP, identifying a subgroup of good outcome patients that unexpectedly also show an enrichment in other myeloid cells. In summary, our results illustrate different TME landscapes with respect to HGPs. dHGP presents a higher degree of immunocompetence, higher amounts of Collagen 1 as well as lesser presence of myeloid cell populations, features that might be influencing on the better prognosis of encapsulated metastases.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are persistent organic pollutants in the environment. While some studies suggest that PFASs may contribute to cancer development, the link between PFAS exposure and cancer risk remains debated.

This dose-response meta-analysis explores the relationship between PFASs and cancer. It employs odds ratio (OR) and standardized mean difference (SMD), along with their 95% confidence interval (CI), to assess the effects of PFASs on cancer risk. Relevant studies were sourced from Web of Science, PubMed, Embase, Medline, and CNKI databases. The dose-response relationship was assessed by the fixed-effects model and least-squares regression.

Forty studies, involving a total of 748,188 participants, were included in this meta-analysis. Out of these, 13 studies were specifically analyzed for the dose-response relationship. Findings revealed that exposure to PFASs, especially PFDA, significantly raises the risk of genitourinary cancers, and PFDA exposure shows a dose-dependent increase in overall and breast cancer risk. Additionally, PFOS exposure is associated with an increased cancer risk, and elevated PFOA levels were significantly observed in breast cancer patients.

The findings suggest that PFAS exposure is a potential cancer risk factor, with the carcinogenic potential of PFDA being dose-dependent.

The online version contains supplementary material available at 10.1007/s40201-024-00899-w.

Cancer is the second leading cause of mortality worldwide. Despite recent advances in cancer treatment including immunotherapy with immune checkpoint inhibitors, new unconventional biomarkers and targets for the detection, prognosis, and treatment of cancer are still in high demand. Tumor cells are characterized by mutations that allow their unlimited growth, program their local microenvironment to support tumor growth, and spread towards distant sites. While a major focus has been on altered tumor genomes and proteomes, crucial signaling molecules such as lipids have been underappreciated. One of these molecules is the membrane phospholipid phosphatidylserine (PS) that is usually found at cytosolic surfaces of cellular membranes but can be rapidly and massively shuttled to the extracellular leaflet of the plasma membrane during apoptosis to serve as a limiting factor for immune responses. These immunosuppressive interactions are exploited by tumor cells to evade the immune system. In this review, we describe mechanisms of immune regulation in tumors, discuss if PS may constitute an inhibitory immune checkpoint, and describe current and future strategies for targeting PS to reactivate the tumor-associated immune system.

Leukotriene B4 (LTB4) plays a crucial role in carcinogenesis by inducing epithelial-mesenchymal transition (EMT), a process associated with tumor progression. The synthesis of LTB4 is mediated by leukotriene A4 hydrolase (LTA4H), and it binds to the receptors BLT1 and BLT2. Dysregulation in LTB4 production is linked to the development of various pathologies. Therefore, the identification or design of inhibitors of LTB4 synthesis or receptor antagonists represents an ongoing challenge. In this context, our laboratory previously demonstrated that alpha-lipoic acid (ALA) inhibits LTA4H. The objective of this study was to evaluate the effect of ALA on the expression of canonical EMT markers and the functional and tumorigenic capacities induced by LTB4 in A549 cells.

The expression of cPLA2, 5LOX, FLAP, LTA4H, BLT1, and LTB4 production in human adenocarcinomic alveolar basal epithelial A549 cells was assessed using Western blot, RT-qPCR, and ELISA, respectively. Subsequently, the expression of canonical EMT markers was evaluated by Western blot. Functional assays were performed to assess cell viability, proliferation, invasion, migration, and clonogenicity using MTT, Western blot, Transwell assays, and colony formation assays, respectively. Results were expressed as median with interquartile range (n≥3) and analyzed using the Kruskal-Wallis or Tukey multiple comparisons tests.

A549 cells express key proteins involved in LTB4 synthesis and receptor binding, including LTA4H and BLT1, and ALA inhibits the production of LTB4. Additionally, LTA4H and BLT1 were detected in lung adenocarcinoma tissue samples. LTB4 was found to induce EMT, whereas ALA treatment enhanced the expression of epithelial markers and reduced the expression of mesenchymal markers. Furthermore, ALA treatment resulted in a decrease in LTB4 levels and attenuated the functional and tumorigenic capacities of A549 cells, including their viability, migration, invasion, and clonogenic potential.

These findings suggest that ALA may offer therapeutic potential in the context of lung cancer, as it could be integrated into conventional pharmacological therapies to enhance treatment efficacy and mitigate the adverse effects associated with chemotherapy. Further studies are warranted to confirm the clinical applicability of ALA as an adjunctive treatment in lung cancer.

Tumor-associated macrophages (TAMs) recapitulate the developmental and homeostatic behaviors of tissue resident macrophages (TRMs) to promote tumor growth, invasion and metastasis. TRMs arise in the embryo and colonize developing tissues, initially to guide tissue morphogenesis and then to form complex networks in adult tissues to constantly search for threats to homeostasis. The macrophage growth factor, colony-stimulating factor-1 (CSF-1), which is essential for TRM survival and differentiation, is also responsible for the development of the unique motility machinery of mature macrophages that underpins their ramified morphologies, migratory capacity and ability to degrade matrix. Two CSF-1-activated kinases, hematopoietic cell kinase and the p110δ catalytic isoform of phosphatidylinositol 3-kinase, regulate this machinery and selective inhibitors of these proteins completely block macrophage invasion. Considering tumors co-opt the invasive capacity of TAMs to promote their own invasion, these proteins are attractive targets for drug development to inhibit tumor progression to invasion and metastasis.

Invasion and metastasis are hallmarks of cancer. In addition to the well-recognized hematogenous and lymphatic pathways of metastasis, cancer cell dissemination can occur via the transcoelomic and perineural routes, which are typical of ovarian and pancreatic cancer, respectively. Macrophages are a universal major component of the tumor microenvironment and, in established tumors, promote growth and dissemination to secondary sites. Here, we review the role of tumor-associated macrophages (TAMs) in cancer cell dissemination and metastasis, emphasizing the diversity of myeloid cells in different tissue contexts (lungs, liver, brain, bone, peritoneal cavity, nerves). The generally used models of lung metastasis fail to capture the diversity of pathways and tissue microenvironments. A better understanding of TAM diversity in different tissue contexts may pave the way for tailored diagnostic and therapeutic approaches.

Aberrant Notch, which is a defining feature of triple-negative breast cancer (TNBC) cells, regulates intercellular communication in the tumor immune microenvironment (TIME). This includes tumor-associated macrophage (TAM) recruitment through Notch-dependent cytokine secretion, contributing to an immunosuppressive TIME. Despite the low response rate of TNBC to immune checkpoint blockade (ICB), here, we report that inhibition of Notch-driven cytokine-mediated programs reduces TAMs and induces responsiveness to sequentially delivered ICB. This is characterized by the emergence of GrB+ cytotoxic T lymphocytes (CTLs) in the primary tumor. A more impressive effect of sequential treatment is observed in the lung where TAM depletion and increased CTLs are accompanied by near-complete abolition of metastases. This is due to (i) therapeutic reduction in Notch-dependent, prometastatic circulating factors released by the primary tumor, and (ii) elevated PD ligand 1 (PD-L1) in lung metastases, rendering them profoundly sensitive to ICB. These findings highlight the potential of combination cytokine inhibition and ICB as an immunotherapeutic strategy in TNBC.

Interleukin-18, a member of the interleukin - 1 family of cytokines, is upregulated in glioma. However, its effects on glioma remain unclear. This study aimed to explore the role and underlying mechanisms of interleukin-18 expression in glioma. Here, we demonstrated that interleukin-18 enhanced resistance to temozolomide by increasing proliferation and inhibiting apoptosis in cultured glioma cells. Further in vivo studies revealed that interleukin-18 promoted temozolomide resistance in BALB/c nude mice bearing tumor. Mechanical exploration indicated that interleukin-18 stimulation could activate the PI3K/AKT signaling pathway in glioma cells, and PI3K inhibition could reduce the temozolomide resistance promoted by interleukin-18. We found that interleukin-18 upregulated CD274 expression in glioma, revealing its potential effects on the microenvironment. Furthermore, we established a tumor xenograft model and explored the therapeutic efficacy of anti-interleukin-18 monoclonal antibody. Targeting interleukin-18 prolonged survival and attenuated CD274 expression in the mice bearing tumor. Combined treatment with anti-interleukin-18 and anti-PD-1 monoclonal antibody showed better efficacy in suppressing tumor growth than either treatment alone in mice bearing tumor. Collectively, these data present that interleukin-18 promotes temozolomide chemoresistance in glioma cells via PI3K/Akt activation and establishes an immunosuppressive milieu by modulating CD274. This study highlights the therapeutic value of interleukin-18 in glioma.

Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which has shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment in cancer therapy, only a minority of patients exhibit a positive response to it. In patients with solid tumors, those who respond well to ICB treatment typically demonstrate an active immune profile referred to as the "hot" (immune-inflamed) phenotype. On the other hand, non-responsive patients may exhibit a distinct "cold" (immune-desert) phenotype, differing from the features of "hot" tumors. Additionally, there is a more nuanced "excluded" immune phenotype, positioned between the "cold" and "hot" categories, known as the immune "excluded" type. Effective differentiation between "cold" and "hot" tumors, and understanding tumor intrinsic factors, immune characteristics, TME, and external factors are critical for predicting tumor response and treatment results. It is widely accepted that ICB therapy exerts a more profound effect on "hot" tumors, with limited efficacy against "cold" or "altered" tumors, necessitating combinations with other therapeutic modalities to enhance immune cell infiltration into tumor tissue and convert "cold" or "altered" tumors into "hot" ones. Therefore, aligning with the traits of "cold" and "hot" tumors, this review systematically delineates the respective immune characteristics, influencing factors, and extensively discusses varied treatment approaches and drug targets based on "cold" and "hot" tumors to assess clinical efficacy.

Inflammation can affect the progression of cancer at tumor sites, such as in osteosarcoma, by intensifying metastasis and complicating outcomes. The current diagnostic methods lack the specificity and sensitivity required for early and accurate detection, particularly in differentiating between inflammation-induced changes and tumor activities. To address this, a novel "hedgehog ball"-shaped nanoprobe, Fe3O4@Au-pep-CQDs, was developed and designed to enhance the detection of caspase-1, a key marker of inflammation. This magnetic nanoprobe facilitates simultaneous fluorescence (FL) and electrochemiluminescence (ECL) detection. Magnetic separation minimizes the quenching of nanoparticles in solution and eliminates the need for frequent electrode replacement in ECL tests, thereby simplifying diagnostic procedures. The experimental results showed that in the detection of caspase-1, the nanoprobe had a detection limit of 0.029 U/mL (FL) and 0.033 U/mL (ECL) and had a dynamic range of 0.05 to 1.0 U/mL. Additionally, the nanoprobe achieved high recovery rates of 94.36 to 102.44% (FL) and 94.36-100.12% (ECL) in spiked biological samples. Furthermore, the nanoprobe's capabilities were extended to in vivo bioimaging to provide direct, intuitive visualization of biological processes. These novel nanoprobes were able to significantly enhance the accurate detection of inflammation at tumor sites, thereby optimizing both diagnostic and therapeutic strategies.

Mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. Cyclooxygenase-2 (COX-2) is a key enzyme involved in inflammatory signaling. While being transiently upregulated upon inflammatory stimuli, COX-2 has been found to be consistently overexpressed in human colorectal cancer and several other malignancies. The association between chronic inflammation and cancer has been revisited: cancer can arise when inflammation fails to resolve. Besides its proinflammatory functions, COX-2 also catalyzes the production of pro-resolving as well as anti-inflammatory metabolites from polyunsaturated fatty acids. This may account for the side effects caused by long term use of some COX-2 inhibitory drugs during the cancer chemopreventive trials. This review summarizes the latest findings highlighting the dual functions of COX-2 in the context of its implications in the development, maintenance, and progression of cancer.

The mediator complex (MED) family is a contributing factor in the regulation of transcription and proliferation of cells, and is closely associated with the development of various types of cancer. However, the significance of the expression levels and prognostic value of MED genes in kidney renal clear cell carcinoma (KIRC) have rarely been reported. The present study analyzed the expression and prognostic potential of MED genes in KIRC. The Search Tool for the Retrieval of Interacting Genes/Proteins was used to construct the protein-protein interaction network (PPI), the Assistant for Clinical Bioinformatics database was used to perform correlation analysis, GEPIA 2 was utilized to draw the Kaplan-Meier plot and analyze prognostic significance and the Tumor Immune Estimation Resource was used to assess the association of MED genes with the infiltration of immune cells in patients with KIRC. A total of 30 MED genes were identified, and among these genes, 11 were selected for the creation of a prognostic gene signature based on the results of a LASSO Cox regression analysis. Furthermore, according to univariate and multivariate analyses, MED7, MED16, MED21, MED25 and MED29 may be valuable independent predictive biomarkers for the prognosis of individuals with KIRC. Furthermore, there were significant differences in the expression levels of MED7, MED21 and MED25 in KIRC among different tumor grades. Additionally, patients with KIRC with high transcription levels of MED7, MED21 and MED29 had considerably longer overall survival times. The expression levels of MED genes were also linked to the infiltration of several immune cells. Overall, MED genes may have potential significance in predicting the prognosis of patients with KIRC.