Tumor Research Articles

The Multifaced Role of Collagen in Cancer Development and Progression

Collagen is a crucial protein in the extracellular matrix (ECM) essential for preserving tissue architecture and supporting crucial cellular functions like proliferation and differentiation. There are twenty-eight identified types of collagen, which are further divided into different subgroups. This protein plays a critical role in regulating tissue homeostasis. However, in solid tumors, the balance can be disrupted, due to an abundance of collagen in the tumor microenvironment, which significantly affects tumor growth, cell invasion, and metastasis. It is important to investigate the specific types of collagens in cancer ECM and their distinct roles in tumor progression to comprehend their unique contribution to tumor behavior. The diverse pathophysiological functions of different collagen types in cancers illustrate collagen’s dual roles, offering potential therapeutic options and serving as prognostic markers.

Cancer Cell’s Achilles Heels: Considerations for Design of Anti-Cancer Drug Combinations

Loss of function screens using shRNA (short hairpin RNA) and CRISPR (clustered regularly interspaced short palindromic repeats) are routinely used to identify genes that modulate responses of tumor cells to anti-cancer drugs. Here, by integrating GSEA (Gene Set Enrichment Analysis) and CMAP (Connectivity Map) analyses of multiple published shRNA screens, we identified a core set of pathways that affect responses to multiple drugs with diverse mechanisms of action. This suggests that these pathways represent “weak points” or “Achilles heels”, whose mild disturbance should make cancer cells vulnerable to a variety of treatments. These “weak points” include proteasome, protein synthesis, RNA splicing, RNA synthesis, cell cycle, Akt-mTOR, and tight junction-related pathways. Therefore, inhibitors of these pathways are expected to sensitize cancer cells to a variety of drugs. This hypothesis was tested by analyzing the diversity of drugs that synergize with FDA-approved inhibitors of the proteasome, RNA synthesis, and Akt-mTOR pathways. Indeed, the quantitative evaluation indicates that inhibitors of any of these signaling pathways can synergize with a more diverse set of pharmaceuticals, compared to compounds inhibiting targets distinct from the “weak points” pathways. Our findings described here imply that inhibitors of the “weak points” pathways should be considered as primary candidates in a search for synergistic drug combinations.

Curcumin: Epigenetic Modulation and Tumor Immunity in Antitumor Therapy.

Curcumin is the main ingredient of the Chinese herbal turmeric rhizome, used to treat tumors, diabetes, inflammation, neurodegenerative diseases, cardiovascular diseases, metabolic syndrome, and liver diseases. The antitumor effects of curcumin have received even more attention. One of the main mechanisms of antitumor effects includes inhibition of tumor invasion and migration, induction of tumor cell apoptosis, and inhibition of various cell signaling pathways. It has been found that the antitumor biological activity of curcumin in the body is associated with epigenetic mechanisms. That also implies that curcumin may act as a potential epigenetic modulator to influence the development of tumor diseases. The immune system plays an essential role in the development of tumorigenesis. Tumor immunotherapy is currently one of the most promising research directions in the field of tumor therapy. Curcumin has been found to have significant regulatory effects on tumor immunity and is expected to be a novel adjuvant for tumor immunity. This paper summarizes the antitumor effects of curcumin from four aspects: molecular and epigenetic mechanisms of curcumin against a tumor, mechanisms of curcumin modulation of tumor immunotherapy, reversal of chemotherapy resistance, and novel drug delivery system of curcumin, which provide new directions for the development of new antitumor drugs.

Gemcitabine-Loaded Microbeads for Transarterial Chemoembolization of Rabbit Renal Tumor Monitored by 18F-FDG Positron Emission Tomography/X-Ray Computed Tomography Imaging

Background/Objectives: The purpose of this study was to develop the gemcitabine-loaded drug-eluting beads (G-DEBs) for transarterial chemoembolization (TACE) in rabbit renal tumors and to evaluate their antitumor effect using 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography/X-ray computed tomography (18F-FDG PET/CT). Methods: DEBs were prepared by polyvinyl alcohol-based macromer crosslinked with N-acryl tyrosine and N,N′-methylenebis(acrylamide). Gemcitabine was loaded through ion change to obtain G-DEBs. Their particle size and drug release profile were characterized. VX2 tumors were implanted in the right kidney of rabbits to establish the renal tumor model. The tumor-bearing rabbits received pre-scan by 18F-FDG PET/CT, followed by targeted transarterial injection of G-DEBs under digital subtraction angiography (DSA) guidance. The rabbits received another 18F-FDG PET/CT scan 10 or 14 days after the treatment. The therapeutic effect was further validated by histopathological analysis of the dissected tumors. Results: The average particle size of the microspheres was 58.06 ± 0.50 µm, and the polydisperse index was 0.26 ± 0.002. The maximum loading rate of G-DEBs was 18.09 ± 0.35%, with almost 100% encapsulation efficiency. Within 24 h, GEM was eluted from G-DEBs rapidly and completely, and more than 20% was released in different media. DSA illustrated that G-DEBs were delivered to rabbit renal tumors. Compared with the untreated control group with increased tumor volume and intense 18F -FDG uptake, the G-DEBs group showed significant reductions in tumor volume and maximum standard uptake value (SUVmax) 10 or 14 days after the treatment. Histopathological analysis confirmed that the proliferating area of tumor cells was significantly reduced in the G-DEBs group. Conclusions: Our results demonstrated that G-DEBs are effective in TACE treatment of rabbit VX2 renal tumors, and 18F-FDG PET/CT provides a non-invasive imaging modality to monitor the antitumor effects of TACE in renal tumors.

Pivotal Role of the Intracellular Microenvironment in the High Photodynamic Activity of Cationic Phthalocyanines.

To investigate the influence of phthalocyanine aggregation on their photodynamic activity, a series of six cationic water-soluble zinc(II) phthalocyanines bearing from four to sixteen 4-((diethylmethylammonium)methyl)phenoxy substituents was synthesized. Depending on their structure, the phthalocyanines have different aggregation behaviors in phosphate buffer solutions ranging from fully assembled to monomeric states. Remarkably, independent of aggregation in buffer, very high photodynamic efficiencies against the tumor cell lines MCF-7 and MDA-MB-231 in the nanomolar range were found for all investigated phthalocyanine, and the IC50(light) varied from 27 to 358 nM (3.5 J/cm2, 660 nm) with IC50(dark)/IC50(light) ratios up to ∼3700. This is due to the intracellular disassembly of aggregated phthalocyanines with the formation of monomeric photoactive forms, as demonstrated by fluorescence microscopy. Indeed, the interaction of aggregated phthalocyanines with serum proteins in a buffer resulted in the disassembly of nonluminescent aggregate species with the release of photoactive monomers bound to protein macromolecules.

Impact of T Cell Exhaustion and Stroma Senescence on Tumor Cell Biology and Clinical Outcome of Head and Neck Squamous Cell Carcinomas

Head and neck squamous cell carcinomas (HNSCC) have an overall poor prognosis, especially in locally advanced and metastatic stages. In most cases, multimodal therapeutic approaches are required and show only limited cure rates with a high risk of tumor recurrence. Anti-PD-1 antibody treatment was recently approved for recurrent and metastatic cases but to date, response rates remain lower than 25%. Therefore, the investigation of the immunological tumor microenvironment and the identification of novel immunotherapeutic targets in HNSCC is of paramount importance. In our study, we used tissue samples of n = 116 HNSCC patients for the immunohistochemical detection of the intratumoral and peritumoral expression of T cell exhaustion markers (PD-1, LAG-3, TIM-3) on tumor infiltration leukocytes (TIL), as well as the expression level of stromal senescence markers (IL-8, MMP-3) on tumor-associated fibroblasts. The clinical parameter of the vitamin D serum status as well as the histopathological HPV infection status of the tumor was correlated with the expression rates of the biomarkers and the overall patient survival. An increased peritumoral and intratumoral expression of the biomarkers PD-1 and TIM-3 significantly correlated with improved overall patient survival. A high peritumoral expression of LAG-3 correlated with better overall survival. A positive HPV tumor status correlated with a significantly elevated expression of PD-1 and TIM-3. Biomarkers of stromal senescence showed no influence on the patient outcome. However, the vitamin D serum status showed no influence on patient outcomes or biomarker expressions. Our study identified PD-1, LAG-3, and TIM-3 as promising targets of a therapeutic strategy targeting the tumor microenvironment in HNSCC, particularly among HPV-positive patients, where a higher expression of these checkpoints correlated with an improved overall survival. These findings support the potential of antibodies targeting these immune checkpoints to enhance treatment efficacy, especially in the context of bispecific targeting.

A Novel Effective Models for Identifying BRCA Patients and Optimizing Clinical Treatments.

This study aimed to develop an effective model that identifies high-risk breast cancer (BRCA) patients and optimizes clinical treatments. This study includes five public datasets, TCGA-BRCA as the training dataset and other cohorts as the validation datasets. Machine learning algorithms for finding key tumor-associated immune gene pairs (TAIGPs). These TAIGPs were used to construct tumor-associated immune gene pair index (TAIGPI) by multivariate analysis and further validated on the validation datasets. In addition, the differences in clinical prognosis, biological characteristics, and treatment benefits between high and low TAIGPI groups were further analyzed. The TAIGPI was established by 36 TAIGPs. Better clinical outcomes in the low TAIGPI patients, with consistent results, were also obtained in the validation datasets. The study showed that patients in the low TAIGPI group had a high infiltration of immune cells and low proliferative activity of tumor cells. In contrast, patients in the high TAIGPI group exhibited low infiltration of immune cells and high proliferative activity of tumor cells. In addition, patients in the low TAIGPI group are more likely to benefit from chemotherapy, adjuvant chemotherapy, or immunotherapy. The TAIGPI can be an effective predictive strategy for the clinical prognosis of breast cancer patients, providing new insights into personalized treatment options for breast cancer patients.

CAR-T Cell Therapy: An Advancement in Conventional Cancer Treatment Methods

Neoplastic tissues, often known as cancerous malignant tumors, are essentially just collections of aberrant cells that can invade nearby tissues, travel to lymph nodes, and even reach other organs. CAR-T cells, or genetically engineered T cells, express the CAR protein on their surface. A recognition region on the exterior and a signaling region on the inside make up the CAR protein. The antigen plays a crucial role in the development of CAR-T cells. Targeting tumor-specific or tumor-associated antigens that are either exclusively present on tumor cells or increased on the surface of cancer cells is the usual goal of CAR-T cell therapy. The FDA and EMA have approved the commercial sale of CAR T cell treatment out of all the different types of ACTs. Six different drugs have been approved in the US and Europe to treat seven different types of B cell cancer. Patients must be screened by their physicians before considering CAR-T cell therapy. Patients may need to go through therapeutic preparatory procedures including lymphodepletion and bridging therapy before receiving CAR-T cell treatment. CAR T cell therapy's remarkable outcomes have altered dire prognoses and prevented several fatalities from severe cancers. However, an increasing amount of clinical experience is exposing their limitations. Currently, CAR-T cell therapy is mostly used to treat certain blood cancer types. Nevertheless, fresh research is being planned to determine how to improve the effectiveness, lower the cost, and expand the potential applications of therapies. Research is now being done to increase the safety and efficacy of CAR-T cell treatment. Keywords: Chimeric antigen receptor, Major Histocompatibility Complex, Tumor-associated antigen, Cytokine storm syndrome, Cluster of differentiation.

HDACi combination therapy with IDO1i remodels the tumor microenvironment and boosts antitumor efficacy in colorectal cancer with microsatellite stability

BackgroundImmunotherapy for colorectal cancer (CRC) with microsatellite stability (MSS) and mismatch repair proficiency (pMMR) has shown limited success in clinical trials. The combination of immunomodulators and immune checkpoint inhibitors (ICIs) is a potential strategy for treating CRC.MethodsHistone deacetylase (HDAC) and indoleamine 2,3-dioxygenase 1 (IDO1) expression in CRC tissues and adjacent normal tissues was analyzed via database analysis, immunohistochemistry, and western blotting. A nanodrug designated as NP-I/P was subsequently formulated, encapsulating an IDO1 inhibitor (IDO1i; namely, epacadostat) and an immunomodulatory HDAC inhibitor (HDACi; namely, panobinostat). The antitumor efficacy of the nanoparticles and their effects on tumor microenvironment features were evaluated via in vitro and in vivo experiments.ResultsIn the present study, we found that HDAC overexpression and IDO1 expression were attenuated in MSS/pMMR CRC. Thus, a nanodrug designated as NP-I/P was formulated to encapsulate epacadostat and panobinostat. In vitro, NP-I/P treatment promoted the apoptosis of tumor cells and induced the release of damage-associated molecular patterns, thereby leading to cell death–associated immune activation. The in vivo results revealed that NP-I/P treatment reversed the immunosuppressive phenotype of the microenvironment by inducing tumor immunogenic cell death (ICD), promoting CD8+ T cell infiltration, and reducing the numbers of Tregs, tumor-associated macrophages, and myeloid-derived suppressor cells. Finally, the results of the patient-derived xenograft and patient-derived organoid models demonstrated that NP-I/P treatment triggered tumor cell death and modulated the immune microenvironment in human CRC.ConclusionThe combination of IDO1 and HDAC inhibitors represents a promising strategy for CRC treatment, and NP-I/P is a candidate for clinical trials.

Phosphocholine inhibits proliferation and reduces stemness of endometrial cancer cells by downregulating mTOR-c-Myc signaling

BackgroundEndometrial cancer (EC) represents a serious health concern among women globally. Excessive activation of the protooncogene c-Myc (c-Myc) is associated with the proliferation and stemness of EC cells. Phosphocholine (PC), which is synthesized by choline kinase alpha (CHKA) catalysis, is upregulated in EC tumor tissues. The present study aimed to investigate the effect of PC accumulation on EC cells and clarify the relationship between PC accumulation and c-Myc activity in EC.MethodsThe c-Myc and CHKA expression in EC tumor tissues were examined using immunohistochemistry. Cell Counting Kit-8 assay, colony formation assay, flow cytometry, western blotting, BrdU staining, and tumorsphere formation assay were used to assess the effect of PC accumulation on EC cells. The mechanism by which PC accumulation inhibits c-Myc was evaluated using RNA-sequencing. Patient-derived organoid (PDO) models were utilised to explore the preclinical efficacy of PC against EC cells.ResultsPC accumulation suppressed EC cell proliferation and stemness by inhibiting the activation of the mammalian target of rapamycin (mTOR)-c-Myc signaling. PC accumulation promoted excessive reactive oxygen species production, which reduced the expression of GTPase HRAS. This, in turn, inhibited the mTOR-c-Myc axis and induced EC cell apoptosis. Finally, PC impeded proliferation and downregulated the expression of the mTOR–MYC signaling in EC PDO models.ConclusionsPC accumulation impairs the proliferation ability and stem cell characteristics of EC cells by inhibiting the activated mTOR-c-Myc axis, potentially offering a promising strategy to enhance the efficacy of EC clinical therapy through the promotion of PC accumulation in tumor cells.

A Catch-Release Strategy for the Genomics-Driven Discovery of Antiproliferative Furan-Functionalized Peptides.

Furan-functionalized peptides are of significant pharmacological interest due to their pronounced bioactivities and unique potential for orthogonal bioconjugation and derivatization. However, naturally occurring peptides with furyl side chains are exceedingly rare. This study presents a streamlined method to predict and assess the microbial production of peptides incorporating 3-furylalanine (Fua) moieties. The approach integrates genome mining and the reversible, chemoselective tagging of furyl residues, utilizing their unique Diels-Alder reactivity, for mass spectrometry-guided identification of candidate compounds. By employing the rhizonin Fua synthase as a bioinformatic handle and through heterologous reconstitution of Fua biosynthesis, we identified previously unknown Fua biosynthetic pathways in diverse bacterial phyla, including actinomycetes, cyanobacteria, actinobacteria, and g-proteobacteria, suggesting that Fua-containing peptides are remarkably widely distributed. Metabolic profiling by reversible tagging facilitated the detection of native Fua-containing metabolites. The successful adaptation of this method for solid support enabled the direct enrichment of furyl-substituted peptides from complex mixtures. This multi-pronged approach enabled the discovery and characterization of two novel families of Fua cyclopeptides (rubriamides and typhamides) with potent antiproliferative effects against human tumor cells and nematodes. The innovative catch-and-release strategy, in conjunction with genome mining, represents a valuable tool for the discovery of new furan-substituted natural products.

Spatiotemporal Mapping of Lymphatic Metastases in Gastric Cancer Using Tumor-Trackable and Enzyme-Activatable Near-Infrared Fluorescent Nanoprobes.

Sentinel lymph node biopsy holds significant importance in cancer management, yet the challenge persists in early detection and precise resection of metastasis lymph nodes (LNs) due to the absence of specific and sensitive optical probes. This study reports metastatic LN reporters (MLRs) with an activatable optical output for accurate spatiotemporal mapping of lymphatic metastases in gastric cancer. MLRs are self-assembled entities incorporating mixed amphiphiles with a lipophilic tail and a tumor-targeting ligand or a fluorescent moiety that is caged with a switch cleavable by tumor-specific β-galactosidase (β-Gal). After draining into LNs, MLRs selectively activate their near-infrared fluorescence in the presence of spreading tumor cells. In orthotopic gastric cancer mouse models, the representative reporter MLR1 distinguishes macro/micrometastatic LNs from benign LNs and enables early detection of skip LNs metastasis patterns in a spatial-dependent manner. Such an active sensing mechanism provides a high level of sensitivity and specificity comparable to those of flow cytometry analysis. In surgically resected patient specimens, MLR1 differentiates cancerous tissues and metastatic LNs from normal tissues and benign LNs within 1 h. This study thus presents NIRF nanoprobes that permit facile detection of LN metastases in GC patient samples and highlights a generic translatable nanoprobe design for understanding metastatic progression.

Molecular aspects of predicting recurrence of retroperitoneal extraorgan liposarcomas

Purpose of the study. The aim of the work was to optimize the prognosis of recurrences of retroperitoneal extraorgan liposarcomas of various degrees of differentiation by detecting microRNAs (miRNAs) of tumor cells with differential expression depending on the course of the malignant disease.Materials and methods. The study was conducted on 96 patients: 19 patients with lipomas and 77 patients with retroperitoneal extraorgan liposarcomas. Tissue samples were obtained during the operation. Among patients with malignant diseases, highly differentiated liposarcoma (VDLS) was detected in 51 patients, and dedifferentiated (DDLS) in 26 patients. miRNA expression levels in tumor cells were determined using real-time PCR.Results. During the follow-up period, relapses of malignant disease were detected in 25 (32,5%) people: 13 (25,5%) among patients with VDLS and 12 (46,2%) among patients with DDLS. In DDLS, characterized by a more aggressive course, there was an increased level of expression of miRNA155, -21, -26a2 and a decrease in expression of miRNA15a and -34 compared with patients with VDLS. In patients with recurrent retroperitoneal liposarcomas, the expression of miRNA15a was initially 83% lower in tumor cells of surgical samples (p<0,001), iRNA34 by 79% (p< 0,001), and the expression activity of miRNA155 was 7,54 times higher (p<0,001) and miRNA26a2 by 6,93 times (p<0,001).Conclusion. The determination of the expression of miRNA155, -26a2, -34, -15a in tumor cells during surgical treatment of patients with retroperitoneal liposarcomas is an effective way to assess the risk of recurrence and is relevant for determining the tactics of further treatment of patients.

Rotenone, Rhodamine 123 and Janus Green Induce Damage to Nuclear DNA in Ascites Tumor Cells from Mice, Rotenone and Rhodamine in X-Irradiated Cells Contribute to the Maintenance of Genome Integrity

Rotenone, Rhodamine 123 and Janus Green Induce Damage to Nuclear DNA in Ascites Tumor Cells from Mice, Rotenone and Rhodamine in X-Irradiated Cells Contribute to the Maintenance of Genome Integrity

Saliva as a sample for liquid biopsy: A review

This paper reviews the recent advancements in liquid biopsy, focusing on its potential application in oral squamous cell carcinoma. Liquid biopsy, a non-invasive technique, offers a promising alternative to traditional biopsy methods by analyzing circulating tumor cells, exosomes, and circulating tumor DNA in bodily fluids like blood and saliva.The study highlights the advantages of saliva as a liquid biopsy substrate, including its ease of collection, non-invasive nature, and the presence of valuable biomarkers. Several potential markers for OSCC detection in saliva are discussed, such as somatic mutations, viral DNA, microRNAs, and protein biomarkers.While liquid biopsy holds great promise, challenges remain in terms of sensitivity, specificity, and standardization of techniques. Further research is needed to develop more reliable and cost-effective methods for analysing these biomarkers and translating them into clinical practice. By overcoming these limitations, liquid biopsy can revolutionize the early detection, diagnosis, and monitoring of OSCC, leading to improved patient outcomes.

Engineering a Near-Infrared Spiro-Based Aggregation-Induced Emission Luminogen for DNAzyme-Sensitized Photothermal Therapy with High Efficiency and Accuracy.

Aggregation-induced emission luminogen (AIEgens)-based photothermal therapy (PTT) has grown into a sparkling frontier for tumor ablation. However, challenges remain due to the uncoordinated photoluminescence (PL) and photothermal properties of classical AIEgens, along with hyperthermia-induced antiapoptotic responses in tumor cells, hindering satisfactory therapeutic outcomes. Herein, a near-infrared (NIR) spiro-AIEgen TTQ-SA was designed for boosted PTT by auxiliary DNAzyme-regulated tumor cell sensitization. TTQ-SA with a unique molecular structure and packing mode was initially fabricated, endowing it with a strong AIE effect, favorable PL quantum yield, and good photothermal performance. DNAzyme, as a gene silencing tool, could alleviate antiapoptosis response during PTT. By integrating TTQ-SA and DNAzyme into folate-modified poly(lactic-co-glycolic acid) (PLGA) polymer, the as-fabricated nanosystem could promote cell apoptosis and sensitize tumor cells to PTT, thereby maximizing the therapeutic outcomes. With the combination of spiro-AIEgen-based PTT and DNAzyme-based gene silencing, the as-designed nanosystem showed promising NIR and photothermal imaging abilities for tumor targeting and demonstrated significant cell apoptotic, antitumor, and antimetastasis effects against orthotopic breast cancer. Furthermore, a synergistic antitumor effect was realized in spontaneous MMTV-PyMT transgenic mice. These findings offer new insights into AIEgen-based photothermal theranostics and DNAzyme-regulated tumor cell sensitization, paving the way for synergistic gene silencing-PTT nanoplatforms in clinical research.

Antiproliferative Activity and Molecular Docking Analyses of Sesquiterpene Lactones Obtained from Activity-Directed Isolation of Centaurea saligna (K.Koch) Wagenitzin Neoplastic Cells.

Secondary metabolites obtained from plants are among the most commonly encountered chemotherapeutics used in cancer treatment. Plants contain thousands of metabolites; therefore, it is important to reach the compound primarily responsible for activity by fractionating plant extracts through activity-guided isolation. The cytotoxic activities of C. saligna fractions, sub-fractions, and all pure compounds obtained from the plant were investigated in vitro using MCF-7 (human breast cancer), HeLa (human cervical cancer), and PC-3 (prostate cancer) cell lines. Eighteen compounds were isolated from C. saligna, comprising eight sesquiterpene lactones, three flavonoids, five lignans, and two phenolic compounds, with their structures elucidated through 1H-NMR, 13C-NMR, and HMBC spectroscopic techniques. The molecular docking scores of the pure compounds obtained from these sub-fractions were determined using both AutoDock and AutoDock Vina programs. It has been proven that the affinities of linichlorin B and aguerin B for Bcl-2 are higher than those of other compounds, considering the calculated Ki values and placement scores. Notable activities of linichlorin B, cynaropicrin, and aguerin B (with IC50 values of 13.67μg/ml, 6.79μg/ml, and 3.46μg/ml, respectively) were detected in the PC-3 cell line; aguerin B demonstrated activity most comparable to the standard anticancer agent doxorubicin. Likewise, linichlorin B, aguerin B, and cynaropicrin demonstrated notable efficacy in the HeLa and MCF-7 cell lines, as reported by the American National Cancer Institute. Aguerin B, linichlorin B, and cynaropicrin are projected to serve as promising novel chemotherapeutic agents for cancer therapy.

Soluble TREM2 drives triple-negative breast cancer progression via activation of the AKT pathway.

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a key role in immune regulation, particularly within tumor-associated macrophages (TAMs). In triple-negative breast cancer (TNBC), TREM2+ TAMs have been shown to modulate the tumor microenvironment, but the role of its soluble form: soluble triggering receptor expressed on myeloid cells 2 (sTREM2), produced through proteolytic cleavage, remains unclear. In this study, we investigated the effects of sTREM2 on TNBC progression. In vitro, treatment of TNBC cells with recombinant sTREM2 or sTREM2-containing culture supernatant significantly enhanced cell proliferation, invasion, and migration. These effects were further confirmed by the use of TREM2-neutralizing antibodies, which abrogated sTREM2's tumor-promoting activities. In vivo, peri-tumoral injections of recombinant sTREM2 led to a notable acceleration of tumor growth in mouse models. Mechanistically, we found that the effects of sTREM2 were mediated through its binding to the TG2 protein in 4T1 cells, thereby activating the AKT signaling pathway. Collectively, our findings suggest that sTREM2 drives TNBC progression by enhancing critical tumor cell functions, positioning it as a potential therapeutic target for TNBC treatment.

Synergistic Target-Attacking Tumor Cells and M2 Macrophages via a Triple-Responsive Nanoassembly for Complete Metastasis Blocking.

Collaboration of cancerous cells and microenvironment is the root for tumor spreading, leading to difficulty in complete metastasis blockage via mono-intervention. Herein, a triple-responsive nanoassembly is designed for orienting tumor cells and migration-driving M2 tumor associated macrophages (TAMs) in microenvironment for efficient anti-metastatic therapy. Structurally, a reactive oxygen species (ROS)-responsive crosslinked short-chain polyquaternium is synthesized to bridge graphene oxide (GO) scaffold with apolipoprotein A-I crown via borate-crosslinking, electrostatic adherence, and coordinative coupling. The protein-crowning polymeric GO nanoparticles could give multimodal shielding and triple-responsive release of doxorubicin and Snail-targeted siRNA. Tailor-made apolipoprotein A-I crown fulfills nanoparticles synergistically attacking tumor cells and M2 TAMs via binding with overexpressed scavenger receptors. The findings witness the targeted accumulation and potent cytotoxicity of the hybrid nanoparticles for M2 TAMs and tumor cells; especially, elimination of M2 TAMs in tumor microenvironment holds back Snail-enhancing transforming growth factor (TGF)-β signal pathway, which collaborates with Snail silencing in tumor cells to reverse epithelial mesenchymal transition (EMT) and metastasis-promoting niche. Collectively, the synergistic targeting therapeutic platform could provide a promising solution for metastatic tumor treatment.

TLS and immune cell profiling: immunomodulatory effects of immunochemotherapy on tumor microenvironment in resectable stage III NSCLC

BackgroundThe use of programmed death-1 (PD-1) inhibitors in the neoadjuvant setting for patients with resectable stage III NSCLC has revolutionized this field in recent years. However, there is still 40%-60% of patients do not benefit from this approach. The complex interactions between immune cell subtypes and tertiary lymphoid structures (TLSs) within the tumor microenvironment (TME) may influence prognosis and the response to immunochemotherapy. This study aims to assess the relationship between immune cells subtypes and TLSs to better understand their impact on immunotherapy response.MethodsThis study initially compared the tertiary lymphoid structures (TLSs) density among patients who underwent immunochemotherapy, chemotherapy and upfront surgery using 123 tumor samples from stage-matched patients. Multiplex immunohistochemistry (mIHC) was employed to analyze the spatial distribution of PD-L1+CD11c+ cells and PD1+CD8+ T cells within TLSs. Cytometry by time-of-flight (CyTOF) was used to assess immune cell dynamics in paired biopsy and resection specimens from six patients who underwent immunochemotherapy. Key immune cells were validated in newly collected samples using flow cytometry, mIHC, and in vitro CAR-T cells model.ResultsPatients who underwent neoadjuvant chemotherapy or immunochemotherapy exhibited increased TLSs compared to those who opted for upfront surgery. The TLS area-to-tumor area ratio distinguished pCR+MPR and NR patients in the immunochemotherapy group. Spatial analysis revealed variations in the distance between PD-L1+CD11c+ cells and PD1+CD8+ T cells within TLSs in the immunochemotherapy group. CyTOF analysis revealed an increase in the frequency of key immune cells (CCR7+CD127+CD69+CD4+ and CD38+CD8+ cells) following combined therapy. Treatment responders exhibited an increase in CCR7+CD4+ T cells, whereas CD38+CD8+ T cells were associated with compromised treatment effectiveness.ConclusionsImmunochemotherapy and chemotherapy increase TLSs and granzyme B+ CD8+ T cells in tumors. The TLS area-to-tumor ratio distinguishes responders from non-responders, with PD-L1+ dendritic cells near CD8+PD-1+ T cells linked to efficacy, suggesting that PD-1 inhibitors disrupt harmful interactions. Post-immunochemotherapy, CD8+ T cells increase, but CD38+CD8+ T cells show reduced functionality. These findings highlight the complex immune dynamics and their implications for NSCLC treatment.