Gastric cancer is a major health concern worldwide. The survival rate of Gastric cancer greatly depends on the stage at which it is diagnosed. Early diagnosis is critical for improving survival outcomes. To improve the chances of early diagnosis, regular screening tests, such as an upper endoscopy or barium swallow, are recommended for individuals at a higher risk due to factors like family history or a previous diagnosis of gastric conditions. Biomarkers can be detected and measured using non-invasive methods such as blood tests, urine tests, breath analysis, or imaging techniques. These non-invasive approaches offer many advantages, including convenience, safety, and cost-effectiveness, making them valuable tools for disease diagnosis, monitoring, and research. Biomarker-based tests have emerged as a useful tool for identifying gastric cancer early, monitoring treatment response, assessing the recurrence risk, and personalizing treatment plans. In this current review, we have explored both classical and novel biomarkers for gastric cancer. We have centralized their potential clinical application and discussed the challenges in Gastric cancer research.

Excessive subendothelial retention of oxidized low-density lipoprotein (oxLDL) and subsequent oxLDL engulfment by macrophages leads to the formation of foam cells and the development of atherosclerosis. Our previous study showed that the plasma level of sialic acid-binding immunoglobulin-like lectin 5 (Siglec-5) was a novel biomarker for the prognosis of atherosclerosis in diabetic patients. However, the role and underlying mechanisms of Siglec-5 in atherosclerosis have not been elucidated.

Diabetic kidney disease (DKD), a severe complication of diabetes marked by deregulated glucose metabolism, remains enigmatic in its pathogenesis. Herein, we delved into the functional role of Dihydrolipoamide S-acetyltransferase (DLAT), a pivotal E2 component of the pyruvate dehydrogenase complex (PDC), in the context of DKD. Our findings revealed a downregulation of DLAT in the kidneys of diabetic patients, correlating inversely with kidney function. Parallel downregulation was observed in both high-fat diet/streptozotocin (HFD/STZ) and db/db mouse models, as well as in human proximal tubular epithelial cells (HK-2) cultured under hyperglycemic conditions. To further elucidate the role of endogenous DLAT in DKD, we employed genetic ablation of Dlat in mouse models. Dlat haploinsufficient mice exhibited exacerbated renal dysfunction, structural damage, fibrosis, and mitochondrial dysfunction under DKD conditions. Consistent with these findings, modulation of DLAT expression in HK-2 cells highlighted its influence on fibrosis, with overexpression attenuating Fibronectin and Collagen I levels, while downregulation exacerbated fibrosis. Mechanistically, we discovered that DLAT activates mitochondria autophagy through the Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, thereby mitigating mitochondrial dysfunction associated with DKD progression. Inhibition of AMPK abrogated the protective effects of DLAT against mitochondrial dysfunction and DKD. Notably, we identified Hyperforin (HPF), a phytochemical, as a potential therapeutic agent. HPF activates DLAT and AMPK, subsequently ameliorating renal dysfunction, injuries, and fibrosis in both in vivo and in vitro models. In summary, our study underscores the pivotal role of DLAT and AMPK in kidney health and highlights the therapeutic potential of HPF in treating DKD.

In severe Placenta Accreta Spectrum (PAS), trophoblasts gain deep access in the myometrium (placenta increta). This study investigated alterations at the fetal-maternal interface in PAS cases using a systems biology approach consisting of immunohistochemistry, spatial transcriptomics and proteomics. We identified spatial variation in the distribution of CD4, CD3 and CD8 T-cells at the maternal-interface in placenta increta cases. Spatial transcriptomics identified transcription factors involved in promotion of trophoblast invasion such as AP-1 subunits ATF-3 and JUN, and NFKB were upregulated in regions with deep myometrial invasion. Pathway analysis of differentially expressed genes demonstrated that degradation of extracellular matrix (ECM) and class 1 MHC protein were increased in increta regions, suggesting local tissue injury and immune suppression. Spatial proteomics demonstrated that increta regions were characterised by excessive trophoblastic proliferation in an immunosuppressive environment. Expression of inhibitors of apoptosis such as BCL-2 and fibronectin were increased, while CTLA-4 was decreased and increased expression of PD-L1, PD-L2 and CD14 macrophages. Additionally, CD44, which is a ligand of fibronectin that promotes trophoblast invasion and cell adhesion was also increased in increta regions. We subsequently examined ligand receptor interactions enriched in increta regions, with interactions with ITGβ1, including with fibronectin and ADAMS, emerging as central in increta. These ITGβ1 ligand interactions are involved in activation of epithelial-mesenchymal transition and remodelling of ECM suggesting a more invasive trophoblast phenotype. In PAS, we suggest this is driven by fibronectin via AP-1 signalling, likely as a secondary response to myometrial scarring.

Acute kidney injury (AKI) represents a critical clinical disease characterized by the rapid decline in renal function, carrying a substantial burden of morbidity and mortality. The treatment of AKI is frequently limited by its variable clinical presentations and intricate pathophysiology, highlighting the urgent need for a deeper understanding of its pathogenesis and potential therapeutic targets. Dual-specific protein phosphatase 5 (DUSP5), a member of the serine-threonine phosphatase family, possesses the capability to dephosphorylate extracellular regulated protein kinases (ERK). DUSP5 has emerged as a pivotal player in modulating metabolic signals, inflammatory responses, and cancer progression, while also being closely associated with various kidney diseases. This study systematically scrutinized the function and mechanism of DUSP5 in AKI for the first time, unveiling a substantial increase in DUSP5 expression during AKI. Moreover, DUSP5 knockdown was observed to attenuate the production of inflammatory factors and apoptotic cells in renal tubular epithelial cells by enhancing AMPK/ULK1-mediated autophagy, thus improving renal function. In a word, DUSP5 knockdown in AKI effectively impede disease progression by activating autophagy. This finding holds promise for introducing fresh perspectives and targets for AKI treatment.

Cell senescence and metabolic reprogramming are significant features of diabetic kidney disease (DKD). However, the underlying mechanisms between cell senescence and metabolic reprogramming are poorly defined. Here, we report that retinoid X receptor α (RXRα), a key nuclear receptor transcription factor, regulates cell senescence and metabolic reprogramming in DKD. Through high-throughput sequencing, bioinformatic analysis and experimental validation, we confirmed the critical role of RXRα in promoting cell senescence and metabolic dysregulation in renal tubular epithelial cells (RTECs) induced by lipid overload. In vivo, in situ injection of AAV9-shRxra into the kidney reduced proteinuria, RTECs senescence and insulin resistance in DKD mice. In vitro, knockdown of RXRα markedly improved G2/M phase arrest and suppressed the expression of senescence-associated secretory phenotypes (SASPs). Protein-protein interaction (PPI) analysis and unbiased bioinformatics were employed to identify the direct interactions between RXRα and the mineralocorticoid receptor (MR), which were subsequently validated through coimmunoprecipitation. Gene network analysis revealed the collaborative regulatory role of RXRα and MR in RTECs senescence. In an accelerated aging mouse model, treatment with a MR antagonist has been shown to inhibite the RXRα/MR signaling, improve RTECs senescence, and reduce interstitial fibrosis and lipid deposition in the kidneys. These findings indicate that inhibition of RXRα/MR signaling could alleviate cell senescence during metabolic disorders. Thus, our study revealed that RXRα/MR signaling serves as a critical regulatory factor mediating the crosstalk between cell senescence and metabolic reprogramming, shedding light on a novel mechanism for targeting cell senescence and metabolic dysregulation in DKD.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by severe organ damage and lacking curative treatment. While various immune cell types, especially dysfunctional B and T cells and neutrophils, have been related with disease pathogenesis, limited research has focused on the role of monocytes in SLE. Increased DNA extracellular traps, apoptosis and necrosis have been related to lupus pathogenesis. Our goal is to analyze the contribution of P-selectin glycoprotein ligand 1 (PSGL-1) in SLE monocytes to disease pathogenesis by investigating the control exerted by PSGL-1 on monocyte apoptosis and DNA extrusion in extracellular traps (METs). Monocytes from active disease patients (aSLE) exhibited reduced levels of PSGL-1. Importantly, lower PSGL-1 levels in SLE monocytes associated with several clinical characteristics, including anti-dsDNA autoantibodies, lupus anticoagulant, clinical lung involvement, and anemia. Monocytes from SLE patients showed higher susceptibility to apoptosis than healthy donors (HD) monocytes and PSGL-1/P-selectin interaction decreased secondary necrosis in HD but not in aSLE monocytes. Regarding METs, aSLE monocytes exhibited higher susceptibility to generate METs than HD monocytes. The interaction of HD monocytes with P-selectin induced Syk activation and reduced the levels of DNA extruded in METs. However, in aSLE monocytes, PSGL-1/P-selectin interaction did not activate Syk or reduce the amount of extruded DNA. Our data suggest a dysfunctional PSGL-1/P-selectin axis in aSLE monocytes, unable to reduce secondary necrosis or the amount of DNA released into the extracellular medium in METs, potentially contributing to lupus pathogenesis.

Endoplasmic reticulum (ER) stress is recognized as a crucial contributor to the progression of traumatic brain injury (TBI) and represents a potential target for therapeutic intervention. This study aimed to assess the potential of J147, a novel neurotrophic compound, in alleviating ER stress by modulating related signaling pathways, thereby promoting functional recovery in TBI. To this end, adult mice underwent controlled cortical impact (CCI) injury to induce TBI, followed by oral administration of J147 one-hour post-injury, with daily dosing for 3 to 7 days. Multiple behavioral assessments were conducted over 35 days, revealing a significant, dose-dependent improvement in neurofunctional recovery with J147 treatment. The neuropathological analysis demonstrated reduced acute neurodegeneration (observed at three days through FJC staining), enhanced long-term neuron survival (H&E and Nissl staining), and improved neuroplasticity (Golgi staining) at 35 days post-TBI. At the molecular level, TBIinduced AMP-activated protein kinase (AMPK) dephosphorylation, sterol regulatory element binding protein-1 (SREBP-1) activation, and upregulation of ER stress marker proteins, including phosphorylated eukaryotic initiation factor-2α (p-eIF2a), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) in perilesional cortex neurons at three days post-injury. Notably, the J147 treatment significantly attenuated AMPK dephosphorylation, SERBP-1 activation, and expression of the ER stress markers. In summary, this study reveals the therapeutic promise of J147 in mitigating secondary brain damage associated with TBI and improving long-term functional recovery by modulating ER stress pathways.

According to morphological features, tumor-infiltrating B cells (TIL-Bs) can be classified as lympho-myeloid aggregates (LMAs) and tertiary lymphoid structures (TLSs). As a disease with high incidence and mortality, research on esophageal squamous cell carcinoma (ESCC) TIL-Bs is still unclear. Thus, we aimed to investigate the prognostic value and functional involvement of TIL-Bs in ESCC. Based on CD20 immunohistochemical staining of 147 ESCC samples, the TIL-Bs at different anatomic subregions (intra-tumor (T), invasive margin (IM) and peri-tumor (P)) were quantified and correlated with survival by Kaplan-Meier analyses. We found that LMAs were widely distributed throughout the whole section and were associated with poor prognosis, especially those located in the T subregion, which was contrary to the positive clinical significance of TLSs. Based on the number of LMAs and TLSs, a four-level immune type was constructed as an independent predictor for survival. Using multiplexed immunofluorescence (mIF) staining, we found that the main phenotype of infiltrating B cells in LMAs was CD20IgDCD27 double-negative (DN) B cells. DN B cells were abundant in ESCC tumor tissue, and their high expression was related to shortened overall survival time. Subsequently, we demonstrate a close relationship between DN B cells and regulatory T cells (Tregs) using single cell RNA-seq data, bulk RNA-seq data and flow cytometry, and verified the spatial proximity of DN B cells and Tregs by mIF staining. Trajectory analysis and flow cytometry revealed that DN B cells highly expressed genes involved in the antigen processing and presentation pathway, such as HLA-DR. The abundance of DN B cells and LMAs in ESCC provides novel potential targets for optimal immunotherapy against ESCC.

Chronic kidney disease (CKD) is a strong risk factor for cardiovascular mortality and morbidity. We hypothesized that a senescent phenotype instigated by uremic toxins could account for early vascular aging (EVA) and vascular dysfunctions of microvasculature in end stage kidney disease (ESKD) patients which ultimately lead to increased cardiovascular complication. To test this hypothesis, we utilized both in vivo, and ex vivo approaches to study endothelial and smooth muscle function and structure, and characterized markers related to EVA in 82 ESKD patients (eGFR <15 ml/min) and 70 non-CKD controls. In vivo measurement revealed no major difference in endothelial function between ESKD and control group, aside from higher stiffness detected in the microcirculation of ESKD participants. In contrast, ex vivo measurements revealed a notable change in the contribution of endothelium-derived factors and increased stiffness in ESKD patients vs. controls. In support, we demonstrated that ex vivo exposure of arteries to uremic toxins such as Trimethylamine N-oxide, Phenylacetylglutamine, or extracellular vesicles from CKD patients impaired endothelial function via diminishing the contribution of endothelium-derived relaxing factors such as nitric oxide and endothelium derived hyperpolarizing factor. Uremic arteries displayed elevated expression of senescence markers (p21CIP1, p16INK4a, and SA-β-gal), calcification marker (RUNX2), and reduced expression of Ki67, sirtuin1, Nrf2, and MHY11 markers, indicating the accumulation of senescent cells and EVA phenotype. Correspondingly, treating uremic vessel rings ex vivo with senolytic agents (Dasatinib + Quercetin) effectively reduced the senescence-associated secretory phenotype and changed the origin of extracellular vesicles. Notably, sex differences exist for certain abnormalities suggesting the importance of biological sex in the pathogenesis of vascular complications. In conclusion, the uremic microvasculature is characterized by a "senescence signature", which may contribute to EVA and cardiovascular complications in ESKD patients and could be alleviated by treatment with senolytic agents.

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor requiring effective treatments. Oncolytic viruses induce anti-tumor responses but have limited efficacy. Apolipoprotein A1 (ApoA1) inhibits inflammation, modulates immunity, and promotes anti-oxidation. This study aims to construct an oncolytic adenovirus (Ad5)-ApoA1 for superior anti-tumor effects. We analyzed ApoA1 expression in tumors and its prognostic significance using public databases. Subsequently, we engineered a recombinant oncolytic adenovirus Ad5-ApoA1 and assessed its replication and oncolytic efficacy in vitro and in nude mice. The impact of Ad5-ApoA1 on the tumor microenvironment of HCC was evaluated through flow cytometry, transcriptome sequencing, single-cell sequencing, and other methodologies. Additionally, mechanisms of immune microenvironment modulation by Ad5-ApoA1 were explored. ApoA1 expression was down-regulated with HCC progression and significantly positively correlated with the prognosis of HCC patients. Ad5-ApoA1 exhibited robust oncolytic activity but showed no therapeutic effect on nude mice. However, it significantly inhibited HCC growth and prolonged the survival period of both healthy-immune and humanized immune-reconstituted NCG mice. Furthermore, Ad5-ApoA1 significantly promoted the expression of IFN-γ and GzmB in CD8 T cells while inhibiting the expression of PD-1 and LAG-3. Notably, the cholesterol content in the CD8 T cells studied was significantly correlated with the expression of PD-1 and LAG-3, with ApoA1 promoting cholesterol efflux and reducing cholesterol levels. Ad5-ApoA1 activates CD8 T cells by promoting large-scale viral replication. High levels of ApoA1 protein expression promote cholesterol efflux, inhibit CD8 T cell depletion, and reduce inflammatory factors, ultimately leading to superior therapeutic effects on hepatocellular carcinoma.

Bone malunion or nonunion leads to functional and esthetic problems and is a major healthcare burden. Activation of bone marrow mesenchymal stem cells (BMSCs) and subsequent induction of osteogenic differentiation by local metabolites are crucial steps for bone healing, which has not yet been completely investigated. Here, we found that lactate levels are rapidly increased at the local injury site during the early phase of bone defect healing, which facilitates the healing process by enhancing BMSCs regenerative capacity. Mechanistically, lactate serves as a ligand for the Olfr1440 olfactory receptor, to trigger an intracellular calcium influx that in turn activates osteogenic phenotype transition of BMSCs. Conversely, ablation of Olfr1440 delays skeletal repair and remodelling, as evidenced by thinner cortical bone and less woven bone formation in vivo. Administration of lactate in the defect area enhanced bone regeneration. These findings thus revealed the key roles of lactate in the osteogenic differentiation of BMSCs, which deepened our understanding of the bone healing process, as well as provided cues for a potential therapeutic option that might greatly improve bone defect treatment.

Epithelial ovarian cancer is a significant global health issue among women. Diagnosis and treatment pose challenges due to difficulties in predicting patient responses to therapy, primarily stemming from gaps in understanding tumor chemoresistance mechanisms. Recent advancements in transcriptomic technologies like single-cell RNA sequencing and spatial transcriptomics have greatly improved our understanding of ovarian cancer intratumor heterogeneity and tumor microenvironment composition. Spatial transcriptomics, in particular, comprises a plethora of technologies that enable the detection of hundreds of transcriptomes and their spatial distribution within a histological section, facilitating the study of cell types, states, and interactions within the tumor and its microenvironment. Studies investigating the spatial distribution of gene expression in ovarian cancer masses have identified specific features that impact prognosis and therapy outcomes. Emerging evidence suggests that specific spatial patterns of tumor cells and their immune and non-immune microenvironment significantly influence therapy response, as well as the behavior and progression of primary tumors and metastatic sites. The importance of spatially contextualizing ovarian cancer transcriptomes is underscored by these findings, which will advance our understanding and therapeutic approaches for this complex disease.

Doxorubicin (DOX) is restricted due to its severe cardiotoxicity. There is still a lack of viable and effective drugs to prevent or treat DOX-induced cardiotoxicity(DIC). Vericiguat is widely used to treat heart failure with reduced ejection fraction. However, it is not clear whether vericiguat can improve DIC. In the present study, we constructed a DIC model using mice and neonatal rat cardiomyocytes and found that vericiguat ameliorated DOX-induced cardiac insufficiency in mice, restored DOX-induced mitochondrial dysfunction in neonatal rat cardiomyocytes, and inhibited the expression of inflammatory factors. Further studies showed that vericiguat improved mitochondrial dysfunction and reduced mtDNA leakage into the cytoplasm by up-regulating PRKG1, which activated PINK1 and then inhibited the STING/IRF3 pathway to alleviate DIC. These findings demonstrate for the first time that vericiguat has therapeutic potential for the treatment of DIC.

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at metastatic stage and typically treated with fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). Few patients benefit from this treatment. Molecular subtypes are prognostic in particularly resectable PDAC and might predict treatment response. This study aims to correlate molecular subtypes in metastatic PDAC with FOLFIRINOX responses using real-world data, providing assistance in counselling patients. We collected 131 RNA-sequenced metastatic biopsies and applied a network-based meta-analysis using published PDAC classifiers. Subsequent survival analysis was performed using the most suitable classifier. For validation, we developed an immunohistochemistry (IHC) classifier using GATA6 and keratin-17 (KRT17), and applied it to 86 formalin-fixed paraffin-embedded samples of advanced PDAC. Lastly, GATA6 knockdown models were generated in PDAC organoids and cell lines. We showed that the PurIST classifier was the most suitable classifier. With this classifier, classical tumors had longer PFS and OS than basal-like tumors (PFS: 216 vs. 78 days, p = 0.0002; OS: 251 vs. 195 days, p = 0.049). The validation cohort showed a similar trend. Importantly, IHC GATA6 patients had significantly shorter survival with FOLFIRINOX (323 vs. 746 days, p = 0.006), but no difference in non-treated patients (61 vs. 54 days, p = 0.925). This suggests that GATA6 H-score predicts therapy response. GATA6 knockdown models did not lead to increased FOLFIRINOX responsiveness. These data suggest a predictive role for subtyping (transcriptomic and GATA6 IHC), though no direct causal relationship was found between GATA6 expression and chemoresistance. GATA6 immunohistochemistry should be seamlessly added to current diagnostics and integrated into upcoming clinical trials.

Extrachromosomal circular DNA (eccDNA) derived from linear chromosomes, are showed typical nucleosomal ladder pattern in agarose gel which as a known feature of apoptosis and demonstrated to be immunogenicity. In systemic lupus erythematosus (SLE) patients, elevated levels of cell-free DNA (cfDNA) can be found in either linear forms or circular forms, while circular ones are much less common and harder to detect. The molecular characteristics and function of circular forms in plasma SLE patients remains elusive. Herein, we characterized the hallmarks of plasma eccDNA in SLE patients, including the lower normalized number and GC content of eccDNA in SLE plasma than in the healthy, and SLE eccDNA number positively correlated with C3 and negatively with anti-dsDNA antibodies. The differential eccGenes (eccDNAs carrying the protein coding gene sequence) of SLE was significantly enriched in apoptosis-related pathways. The artificially synthesized eccDNA with sequences of the PRF1 exon region could promote transcriptional expression of PRF1, IFNA and IFIT3 and inhibit early-stage apoptosis. Plasma eccDNA can serve as a novel autoantigen in the pathogenesis of SLE.

Periodontitis is a chronic inflammatory oral disease that impaired the tooth-supporting apparatus, including gingival tissue destruction and alveolar bone resorption. The initiation of periodontitis is linked to the presence of oral bacteria, particularly P. gingivalis within pathogenic biofilms. Here, we demonstrated the central role of the autophagy regulator Transcription Factor EB (TFEB) in orchestrating autophagy activation and modulating the host immune response against P. gingivalis in periodontitis. Upregulation of TFEB expression at the protein level and heightened nuclear localization occurred during the progressive stages of periodontitis. Functionally, TFEB overexpression emerges as a potent alleviator of periodontitis-associated phenotypes, operating through the activation of autophagy and the inhibition of the NF-κB pathway in both in vivo and in vitro models. In addition, TFEB knockdown exacerbates the inflammatory response by upregulating pro-inflammatory cytokines. The dual regulatory role of TFEB in governing both autophagy and inflammatory responses unveils novel insights into periodontitis pathogenesis, positioning TFEB as a promising therapeutic target for periodontitis intervention.

Pulmonary fibrosis is a chronic interstitial lung disease involving systemic inflammation and abnormal collagen deposition. Dysregulations in lipid metabolism, such as macrophage-dependent lipid catabolism, have been recognized as critical factors for the development of pulmonary fibrosis. However, little is known about the signaling pathways involved and the key regulators. Here we found that triggering receptor expressed on myeloid cells 2 (TREM2) plays a pivotal role in regulating the lipid handling capacities of pulmonary macrophages and triggering fibrosis. By integrating analysis of single-cell and bulk RNA sequencing data from patients and mice with pulmonary fibrosis, we revealed that pulmonary macrophages consist of heterogeneous populations with distinct pro-fibrotic properties, and found that both sphingolipid metabolism and the expression of chemotaxis-related genes are elevated in fibrotic lungs. TREM2, a sensor recognizing multiple lipid species, is specifically upregulated in a subset of monocyte-derived macrophages. Blockade of TREM2 by conventional/conditional knock-out or soluble TREM2 administration can attenuate bleomycin-induced pulmonary fibrosis. By utilizing scRNA Seq and lipidomics, we found that Trem2 deficiency downregulates the synthesis of various sphingomyelins, and inhibits the expression of chemokines such as Ccl2. Together, our findings not only reveal the alterations in lipidomic profiles and the atlas of pulmonary macrophages during pulmonary fibrosis, but also suggest that targeting TREM2, the crucial regulator affecting both pulmonary sphingolipid metabolism and the chemokines secretion, can benefit pulmonary fibrosis patients in the future.

Vascular calcification (VC) poses significant challenges in cardiovascular health. This study employs single-cell transcriptome sequencing to dissect cellular dynamics in this process. We identify distinct cell subgroups, notably in vascular smooth muscle cells (VSMCs), and observe differences between calcified atherosclerotic cores and adjacent regions. Further exploration reveals ID3 as a key gene regulating VSMC function. In vitro experiments demonstrate ID3's interaction with USP1 and E12, modulating cell proliferation and osteogenic differentiation. Animal models confirm the critical role of the USP1/ID3/E12/P21 axis in VC. This study sheds light on a novel regulatory mechanism, offering potential therapeutic targets.

Ongoing research on cellular heterogeneity of Cancer stem cells (CSCs) and its synergistic involvement with tumor milieu reveals enormous complexity, resulting in diverse hindrance in immune therapy. CSCs has captured attention for their contribution in shaping of tumor microenvironment and as target for therapeutic intervention. Recent studies have highlighted cell-extrinsic and intrinsic mechanisms of reciprocal interaction between tumor stroma constituents and CSCs. Therapeutic targeting requires an in-depth understanding of the underlying mechanisms involved with the rate limiting factors in tumor aggressiveness and pinpoint role of CSCs. Some of the major constituents of tumor microenvironment includes resident and infiltrating immune cell, both innate and adaptive. Some of these immune cells play crucial role as adjustors of tumor immune response. Tumor-adjustor immune cell interaction confer plasticity and features enabling tumor growth and metastasis in one hand and on the other hand blunts anti-tumor immunity. Detail understanding of CSC and TME resident immune cells interaction can shape new avenues for cancer immune therapy. In this review, we have tried to summarize the development of knowledge on cellular, molecular and functional interaction between CSCs and tumor microenvironment immune cells, highlighting immune-mediated therapeutic strategies aimed at CSCs. We also discussed developing a potential CSC and TME targeted therapeutic avenue.