A cutting-edge approach in cell-based immunotherapy for combating resistant cancer involves genetically engineered chimeric antigen receptor T (CAR-T) lymphocytes. In recent years, these therapies have demonstrated effectiveness, leading to their commercialization and clinical application against certain types of cancer. However, CAR-T therapy faces limitations, such as the immunosuppressive tumour microenvironment (TME) that can render CAR-T cells ineffective, and the adverse side effects of the therapy, including cytokine release syndrome (CRS). Extracellular vesicles (EVs) are a diverse group of membrane-bound particles released into the extracellular environment by virtually all cell types. They are essential for intercellular communication, transferring cargoes such as proteins, lipids, various types of RNAs, and DNA fragments to target cells, traversing biological barriers both locally and systemically. EVs play roles in numerous physiological processes, with those from both immune and non-immune cells capable of modulating the immune system through activation or suppression. Leveraging this capability of EVs to enhance CAR-T cell therapy could represent a significant advancement in overcoming its current limitations. This review examines the current landscape of CAR-T cell immunotherapy and explores the potential role of EVs in augmenting its therapeutic efficacy.

On a global scale, cancer is a difficult and devastating illness. Several problems with current chemotherapies include cytotoxicity, lack of selectivity, stem-like cell growth, and multi-drug resistance. The most appropriate nanomaterials for cancer treatment are those with characteristics, such as cytotoxicity, restricted specificity, and drug capacity and bioavailability; these materials are nanosized (1-100 nm). Nanodrugs are rarely licenced for therapeutic use despite growing research. These compounds need nanocarrier-targeted drug delivery experiments to improve their translation. This review describes new nanomaterials reported in the literature, impediments to their clinical studies, and their beneficial cancer therapeutic use. It also suggests ways to use nanomaterials in cancer therapy more efficiently and describes the intrinsic challenges of cancer treatment and the different nanocarriers and chemicals that can be utilised for specified tumour targeting. Furthermore, it provides a concise overview of cancer theranostics methods, with a focus on those that make use of nanomaterials. Although nanotechnology offers a great source for future advancements in cancer detection and therapy, there is an emerging need for more studies to address the present barriers to clinical translation.

Cancer cells display an altered metabolic phenotype, characterised by increased glycolysis and lactate production, even in the presence of sufficient oxygen - a phenomenon known as the Warburg effect. This metabolic reprogramming is a crucial adaptation that enables cancer cells to meet their elevated energy and biosynthetic demands. Importantly, the tumor microenvironment plays a pivotal role in shaping and sustaining this metabolic shift in cancer cells. This review explores the intricate relationship between the tumor microenvironment and the Warburg effect, highlighting how communication within this niche regulates cancer cell metabolism and impacts tumor progression and therapeutic resistance. We discuss the potential of targeting the Warburg effect as a promising therapeutic strategy, with the aim of disrupting the metabolic advantage of cancer cells and enhancing our understanding of this complex interplay within the tumor microenvironment.

Cancer has a significant negative social and economic impact on both developed and developing countries. As a result, understanding the onset and progression of cancer is critical for developing therapies that can improve the well-being and health of individuals with cancer. With time, study has revealed, the tumor microenvironment has great influence on this process. Micro and nanoscale engineering techniques can be used to study the tumor microenvironment. Nanoscale and Microscale engineering use Novel technologies and designs with small dimensions to recreate the TME. Knowing how cancer cells interact with one another can help researchers develop therapeutic approaches that anticipate and counteract cancer cells\' techniques for evading detection and fighting anti-cancer treatments, such as microfabrication techniques, microfluidic devices, nanosensors, and nanodevices used to study or recreate the tumor microenvironment. Nevertheless, a complicated action just like the growth and in cancer advancement, and their intensive association along the environment around it that has to be studied in more detail.

The efficacy of immunotherapy for clear cell renal cell carcinoma (ccRCC), especially advanced ccRCC, is limited, presenting a clinical challenge. This limitation is closely tied to the immune regulation network. Understanding the heterogeneity of the tumour microenvironment (TME) is crucial for developing advanced ccRCC therapies. Using publicly available ccRCC data (scRNA-seq, bulk RNA-seq, and somatic mutation data), a multiomics study was performed to explore TME heterogeneity. Three distinct ccRCC immune subtypes were identified through combined scRNA-seq and bulk RNA-seq analysis. A prognostic model based on unique cell signalling molecules in immunosuppressive tumour subtype was validated in the TCGA and CheckMate cohorts. MDK emerged as a critical regulatory gene in the immunosuppressive subtype, predicting a poor ccRCC prognosis and a poor immunotherapy response. MDK promotes M2 macrophage polarization via the MDK-LRP1 interaction, and the inhibition of MDK suppressed M2 polarization. This study revealed the heterogeneity of the ccRCC TME and a reliable prognostic model, shedding light on the vital role of MDK in the immunosuppressive TME and paving the way for optimized ccRCC immunotherapy.

BACKGROUND: The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance.
OBJECTIVE: This research explored the effectiveness of integrating anlotinib (a broad-spectrum tyrosine kinase inhibitor) with programmed death-1 (PD-1) blockade and offers mechanistic insights into more effective strategies for treating HCC.
METHODS: Using patient-derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD-1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time-of-flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples.
RESULTS: The combination of anlotinib with an anti-PD-1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF-1α signaling axis. CD8+ T-cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8+ T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti-PD-1 therapy in patients with HCC.
CONCLUSIONS: Our findings highlight anlotinib\'s potential to augment the efficacy of anti-PD-1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14-mediated CD8+ T-cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology.
CONCLUSIONS: Synergistic effects of anlotinib and anti-PD-1 immunotherapy demonstrated in HCC preclinical models. Anlotinib inhibits TFRC expression via the VEGFR2/AKT/HIF-1α pathway. CXCL14 upregulation via TFRC suppression boosts CD8+ T-cell recruitment. TFRC emerges as a potential biomarker for evaluating prognosis and predicting response to anti-PD-1-based therapies in advanced HCC patients.

BACKGROUND: Human hepatocellular carcinoma (HCC) acquired resistance to anti-cancer agents due to the presence of immunosuppressive tumour microenvironment (TME) established by the interaction between tumour cells and immune populations. New treatment targeting the interaction is urgently needed and clinically beneficial to patients with HCC. This study aims to explore the anti-tumour effect of a Traditional Chinese Medicine formula Siwu Decoction (SWD) and its potential mechanism.
METHODS: The chemical profile of SWD was determined by high-performance liquid chromatography coupled with mass spectrometry. In vitro and in vivo effects of SWD in regressing HCC were assessed. The role of myeloid-derived suppressor cells (MDSCs) in mediating SWD-induced HCC inhibition was determined by adoptive transfer assay. The regulation of SWD-induced interaction between HCC cells and MDSCs was also confirmed both in vitro and in vivo.
RESULTS: SWD dose-dependent inhibited the HCC growth and lung metastasis in an orthotopic growth tumour in mice, without significant toxicity and adverse side effect. SWD induced necroptosis in HCC cells, but did not directly inhibit in vitro culture of MDSCs, instead, SWD-treated HCC cell culture supernatant suppressed MDSCs by inducing its cell apoptosis. The necroptotic response of HCC cells can also suppress the MDSCs population in the TME without reducing circulating MDSCs infiltration into the tumours. Adoptive transfer of MDSCs recovered tumour growth and lung metastasis of HCC in SWD-treated mice. In HCC cells, SWD induced a necroptotic response, and blockade of necroptotic response in HCC cells recovered the MDSCs population in vitro and in vivo, and restored tumour growth and lung metastasis in SWD-treated mice. A combination of SWD improves the anti-HCC efficacy of sorafenib without inducing adverse side effects. Albiflorin, the effective compound of SWD, its anti-HCC manner has been verified to be consistent with that of SWD.
CONCLUSIONS: Our study observed for the first time that SWD can suppress HCC by regulating MDSCs through necroptosis of tumour cells in the TME. The main effective compound of SWD, albiflorin can be a potential adjuvant therapy in the clinical management of human HCC.

Low-grade serous ovarian carcinoma (LGSC) is a rare and lethal subtype of ovarian cancer. LGSC is pathologically, biologically, and clinically distinct from the more common high-grade serous ovarian carcinoma (HGSC). LGSC arises from serous borderline ovarian tumours (SBTs). The mechanism of transformation for SBTs to LGSC remains poorly understood. To better understand the biology of LGSC, we performed whole proteome profiling of formalin-fixed, paraffin-embedded tissue blocks of LGSC (n = 11), HGSC (n = 19), and SBTs (n = 26). We identified that the whole proteome is able to distinguish between histotypes of the ovarian epithelial tumours. Proteins associated with the tumour microenvironment were differentially expressed between LGSC and SBTs. Fibroblast activation protein (FAP), a protein expressed in cancer-associated fibroblasts, is the most differentially abundant protein in LGSC compared with SBT. Multiplex immunohistochemistry (IHC) for immune markers (CD20, CD79a, CD3, CD8, and CD68) was performed to determine the presence of B cells, T cells, and macrophages. The LGSC FAP+ stroma was associated with greater abundance of Tregs and M2 macrophages, features not present in SBTs. Our proteomics cohort reveals that there are changes in the tumour microenvironment in LGSC compared with its putative precursor lesion, SBT. These changes suggest that the tumour microenvironment provides a supportive environment for LGSC tumourigenesis and progression. Thus, targeting the tumour microenvironment of LGSC may be a viable therapeutic strategy. © 2024 The Pathological Society of Great Britain and Ireland.

ARHGAP family genes are often used as glioma oncogenic factors, and their mechanism of action remains unexplained. Our research entailed a thorough examination of the immune microenvironment and enrichment pathways across various glioma subtypes. A distinctive 6-gene signature was developed employing the CGGA cohort, leading to insights into the disparities in clinical characteristics, mutation patterns, and immune cell infiltration among distinct risk categories. Additionally, a unique nomogram was established, grounded on ARHGAPs, with DCA curves illustrating the model\'s prospective clinical utility in guiding therapeutic strategies. Emphasizing the role of ARHGAP30, integral to our model, its impact on glioma severity and the credibility of our risk assessment model were substantiated through RT-qPCR, Western blot analysis, and cellular functional assays. We identified 6 ARHGAP family genes associated with glioma prognosis. Analysis using the Kaplan-Meier method indicated a correlation between elevated risk levels and adverse outcomes in glioma patients. The risk score, linked with tumour staging and IDH mutation status, emerged as an independent factor predicting prognosis. Patients in the high-risk category exhibited increased immune cell infiltration, enhanced tumour mutational burden, more pronounced expression of immune checkpoint genes, and a better response to ICB therapy. A nomogram, integrating the risk score with the pathological features of glioma patients, was developed. DCA analysis and cellular studies confirmed the model\'s potential to improve clinical treatment outcomes for patients. A novel ARHGAP family gene signature reveals the prognosis of glioma.

A hyperactive tumour microenvironment (TME) drives unrestricted cancer cell survival, drug resistance, and metastasis in ovarian carcinoma (OC). However, therapeutic targets within the TME for OC remain elusive, and efficient methods to quantify TME activity are still limited. Herein, we employed an integrated bioinformatics approach to determine which immune-related genes (IRGs) modulate the TME and further assess their potential theragnostic (therapeutic + diagnostic) significance in OC progression. Using a robust approach, we developed a predictive risk model to retrospectively examine the clinicopathological parameters of OC patients from The Cancer Genome Atlas (TCGA) database. The validity of the prognostic model was confirmed with data from the International Cancer Genome Consortium (ICGC) cohort. Our approach identified nine IRGs, AKT2, FGF7, FOS, IL27RA, LRP1, OBP2A, PAEP, PDGFRA, and PI3, that form a prognostic model in OC progression, distinguishing patients with significantly better clinical outcomes in the low-risk group. We validated this model as an independent prognostic indicator and demonstrated enhanced prognostic significance when used alongside clinical nomograms for accurate prediction. Elevated LRP1 expression, which indicates poor prognosis in bladder cancer (BLCA), OC, low-grade gliomas (LGG), and glioblastoma (GBM), was also associated with immune infiltration in several other cancers. Significant correlations with immune checkpoint genes (ICGs) highlight the potential importance of LRP1 as a biomarker and therapeutic target. Furthermore, gene set enrichment analysis highlighted LRP1\'s involvement in metabolism-related pathways, supporting its prognostic and therapeutic relevance also in BLCA, OC, low-grade gliomas (LGG), GBM, kidney cancer, OC, BLCA, kidney renal clear cell carcinoma (KIRC), stomach adenocarcinoma (STAD), and stomach and oesophageal carcinoma (STES). Our study has generated a novel signature of nine IRGs within the TME across cancers, that could serve as potential prognostic predictors and provide a valuable resource to improve the prognosis of OC.