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Results for “Cellular Microenvironment”

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PubMed1991

Analysis of immunosuppressive properties of iris and ciliary body cells and their secretory products.

The anterior chamber of the eye is an immunosuppressive microenvironment as shown experimentally by immune privilege, anterior chamber-associated immune deviation, and inability to display local delayed-type hypersensitivity responses. It recently was reported that both the aqueous humor and the cells of the iris and ciliary body (I-CB) have immune inhibitory properties in vitro, suggesting that these components of the anterior segment might contribute to the unique properties of this microenvironment. To explore the cellular sources of immunosuppressive factors in the anterior chamber, cultures of I-CB cells were established from normal eyes of BALB/c mice. Supernatants were harvested from these cultures and assayed in vitro for their ability to inhibit T-lymphocyte activation. It was found that I-CB cell-derived supernatants profoundly suppressed alloantigen-driven T-cell proliferation (mixed lymphocyte response) and interleukin-2 production by a T-cell hybridoma that responds to stimulator cells bearing I-Ad. The inhibitory activity of I-CB supernatants did not appear to be related to prostaglandins; supernatants of I-CB cells cultured with indomethacin retained their suppressive properties, as did supernatants to which neutralizing antiprostaglandin E2 antibodies had been added. Moreover, suppression by I-CB supernatants was not relieved by antibodies specific for transforming growth factor-beta, even though this cytokine is known to be present in normal aqueous humor. Thus, the identity of the suppressive factor(s) in cultured I-CB cell supernatants remains elusive. Finally, by separating I-CB cell suspensions into bone marrow-derived (T-200-positive) and those not derived from bone marrow (parenchymal) subpopulations with a fluorescence-activated cell sorter, it was determined that the inhibitory activity of I-CB cell suspensions was produced by parenchymal, rather than hematogenous, cells. It is proposed and discussed that inhibitory factors and cytokines secreted by parenchymal I-CB cells contribute to the immunosuppressive qualities of the anterior chamber.

Animals↗

PubMed1988

Polyovular follicles associated with human in vitro fertilization.

Polyovular follicles were found in 61 (24%) of 251 laparoscopies performed for in vitro fertilization. Of 898 follicles that contained at least one oocyte, 76 (8%) were polyovular. When the oocytes from polyovular follicles were assessed by morphologic criteria, it was found that 46 of the follicles contained oocytes that were discordant in maturity. Thus, oocytes can develop at different rates even though they are exposed to the same follicular fluid. It is possible that the microenvironment provided by the cellular investments of oocytes may correlate more precisely with oocyte maturity.

Female↗

PubMed1978

Dissecting the hematopoietic microenvironment. III. Evidence for a positive short range stimulus for cellular proliferation.

Experiments were carried out with the intent of defining the nature of the microenvironmental defect which severely limits erythropoiesis in the spleen of the S1/S1d mouse. Chimeric spleens, half S1/S1d and half congenic +/+, supported erythropoiesis in the +/+ region but not in the S1/S1d region, regardless of which genotype was the irradiated, marrow-injected host animal. Implants of normal marrow stroma within the spleens of irradiated S1/S1d mice also supported normal proportions of erythrocytic and granulocytic hematopoiesis. Implants of normal spleen stroma, particularly the capsular portion, into unirradiated s1/s1d mice stimulated erythropoiesis originating from S1/S1d stem cells within and in the immediate vicinity of the implant. The evidence suggests a short range, stromal erythropoietic stimulatory factor which is lacking in the S1/S1d.

Anemia, Macrocytic↗

PubMed1994

Wound infections.

Wound infections continue to be an important entity in terms of use of time and medical resources. Currently, the following risk factors are known to strongly predispose to wound infection: pre-existing medical illness, prolonged operative time, wound contamination, and contaminated or dirty wounds. Tissue level factors, including the local microenvironment, white cells, and cellular products that mediate inflammation, are important, and their manipulation holds promise for future therapies. For now, the judicious use of antibiotic prophylaxis and organized systems of wound surveillance are the most effective means to reduce the wound infection rate to its pathophysiologically attainable minimum.

Anti-Bacterial Agents↗

PubMedDate not supplied

Cellular activation of the self-quenched fluorescent reporter probe in tumor microenvironment.

The effect of intralysosomal proteolysis of near-infrared fluorescent (NIRF) self-quenched macromolecular probe (PGC-Cy5.5) has been previously reported and used for tumor imaging. Here we demonstrate that proteolysis can be detected noninvasively in vivo at the cellular level. A codetection of GFP fluorescence (using two-photon excitation) and NIRF was performed in tumor-bearing animals injected with PGC-Cy5.5. In vivo microscopy of tumor cells in subdermal tissue layers (up to 160 microm) showed a strong Cy5.5 dequenching effect in GFP-negative cells. This observation was corroborated by flow cytometry, sorting, and reverse transcription polymerase chain reaction analysis of tumor-isolated cells. Both GFP-positive (81% total) and GFP-negative (19% total) populations contained Cy5.5-positive cells. The GFP-negative cells were confirmed to be host mouse cells by the absence of rat cathepsin mRNA signal. The subfraction of GFP-negative cells (2.5-3.0%) had seven times higher NIRF intensity than the majority of GFP-positive or GFP-negative cells (372 and 55 AU, respectively). Highly NIRF-positive, FP-negative cells were CD45- and MAC3-positive. Our results indicate that: 1) intracellular proteolysis can be imaged in vivo at the cellular level using cathepsin-sensitive probes; 2) tumor-recruited cells of hematopoetic origin participate most actively in uptake and degradation of long-circulating macromolecular probes.

Animals↗

PubMed1993

Selective cellular acidification and toxicity of weak organic acids in an acidic microenvironment.

The mean extracellular pH (pHe) within solid tumours has been found to be lower than in normal tissues. Agents which cause intracellular acidification at low pHe might have selective toxicity towards cells in tumours. Weak acids (or their anions) with pKa values in the range of 4-6 have a higher proportion of molecules in the uncharged form at low pHe and can diffuse more rapidly into cells. The effects of organic acids including succinate, monomethyl succinate and malonate to acidify cells have been evaluated under conditions of different pHe in the acidic range. These weak acids caused intracellular acidification of murine EMT-6 and human MGH-U1 cells in a concentration and pHe dependent fashion. At concentrations of 10 mM and above, these acids also caused in vitro cytotoxicity to these cells at low pHe (< 6.5). The rate and extent of cellular acidification caused by these weak acids, and their cytotoxicity at low pHe, were enhanced by exposure to amiloride and 5-(N-ethyl-N-isopropyl)amiloride (EIPA), agents which inhibit Na+/H+ exchange, and hence the regulation of intracellular pH. Acid dependent cytotoxicity was also investigated in a murine solid tumour using the endpoints of growth delay and colony formation in vitro following treatment in vivo. Agents were tested alone or with 15 Gy X-rays to select a population of hypoxic (and presumably acidic) cells. Achievable serum concentrations of succinate were about 1 mM and no antitumour activity of succinate was detected when used in this way. It is concluded that weak acids are selectively taken up into cells, and can cause selective cellular acidification and toxicity, at low pHe in culture. Weak acids that are normal cellular metabolites are not toxic in vivo, but weak acids carrying cytotoxic groups offer the potential for selective uptake and toxicity under the conditions of low pHe that exist in many solid tumours.

Amiloride↗

PubMed1999

SCID-hu mice for the study of human cancer metastasis.

Cancer metastasis involves dynamic and multistep in vivo processes. While generation of metastatic clones requires genetic alterations in cancer cells, subsequent selection of the clones is heavily influenced by interactions with the surrounding tissue microenvironment. To reproduce the complex cellular interactions that occur in human patients is, however, difficult, and has not been achieved using currently available in vitro systems or conventional animal models. The SCID-hu mouse is generated by surgical implantation of human fetal tissues into mutant mice of the severe combined immunodeficient (SCID) phenotype. The unique feature of this model is that the implanted human tissues maintain their normal architecture and function. Therefore implanted human tissues will provide relevant microenvironments for the growth and metastasis of human cancer cells. The SCID-hu mouse model, which was specifically designed for the study of human cancer biology, enables experimental investigation of cellular events involved in cancer metastasis on the basis of interactions between human cancer cells and the human tissue microenvironment. It has been demonstrated that various types of human cancer cell lines generate tumors in implanted human bone marrow and lung, organs frequently involved in metastasis in patients, upon intravenous inoculation. Tumorigenic activity in SCID-hu mice faithfully reflects the clinical features of the original cancer. Tumor formation and selection of high tumorigenic variants occur in a species-specific manner. Furthermore, it was shown that metastatic tumor formation is regulated by both cancer cells and conditions in the host organs. Conditioning of animals by either whole-body irradiation or interleukin 1alpha treatment prior to cancer cell inoculation induced metastatic tumor formation by certain small cell lung cancer (SCLC) cell lines specifically in human bone marrow. A novel gene has been identified by comparing gene expression profiles between high and low tumorigenic SCLC cells in human lung. This gene is preferentially expressed in low metastatic lines, and transfection of the gene into highly metastatic cells results in suppression of metastasis. Recent studies have shown that the gene product is involved in the apoptosis induction pathway. Collectively, our results indicate that the SCID-hu mouse will serve as a unique platform technology with which to investigate cellular events involved in human cancer metastasis, as well as to identify genes playing important roles in the growth and metastasis of human cancer, in the context of interactions between human cancer cells and human tissue environments.

Animals↗

PubMed2026

Stage-Independent Real-Time Subtype Classification and Comprehensive Biopsy Profiling of Urothelial Carcinomas by the Lund Taxonomy System.

Bladder cancer is a heterogeneous malignancy with diverse clinical outcomes, and conventional pathological assessment alone is insufficient to capture its underlying biology. Gene expression profiling can stratify tumors into molecular subtypes with prognostic and predictive potential, but the reliability of transcriptomic classification and its clinical utility remains to be established. The translational/observational UROSCANSEQ study (ISRCTN15459149) prospectively evaluates RNA-based Lund Taxonomy (LundTax) molecular subtype classification in a clinical setting. Among 784 consecutive biopsies collected between 2018 and 2022, RNA sequencing was successful for 90% of all biopsies, encompassing 662 bladder cancer patients with a stage distribution of 48% Ta, 27% T1, 24% ≥T2, and 1% CIS. We demonstrate that the LundTax subtype classification algorithm, applied to individual samples, accurately identifies cancer cell phenotypes with characteristic gene and protein expression patterns in a manner robust to RNA quality, data preprocessing strategies, and batch effects, supporting its clinical feasibility across both non-muscle-invasive and muscle-invasive disease. We further extend the LundTax framework by incorporating single-sample molecular risk scores reflecting tumor grade, proliferation, and progression risk, as well as tumor microenvironment signatures. Both risk scores and overall immune and stromal content in biopsies were significantly associated with an increased risk of clinical progression in noninvasive disease. In a separate analysis of the relative cellular composition of the tumor microenvironment, however, only the fraction of natural killer cells remained significant. Together, the expanded LundTax system provides a comprehensive molecular portrait of individual tumor biopsies. By explicitly separating cancer cell-intrinsic phenotypes, prognostic indexes, and microenvironmental signals, the framework minimizes biological confounding and establishes a strong foundation for future studies evaluating clinical outcomes and treatment responses.

Humans↗

PubMed1991

Molecular mechanisms of tubulointerstitial hypertrophy and hyperplasia.

Adult kidneys, which are principally composed of tubulointerstitium, do not normally regenerate or expand their working pool of functional cells at a very high rate. Loss of kidney tissue, however, can lead to some compensatory renal enlargement. The catalytic forces initiating such exchanges have not been fully articulated by current experimental endeavors. Increasing evidence, nevertheless, does suggest that factors other than simple changes in renal hemodynamics may be involved in this process. Different cellular elements in the tubulointerstitial microenvironment probably modulate changes in tubular enlargement or size through a complex cytokine network. Autocrine and paracrine stimulation of enlargement by different local growth factors also seem to play a pivotal role. After binding to cellular receptors, these factors activate signal transduction pathways resulting in expression of immediate early genes, which by themselves can synchronize the expression of subsequent genes through the medium of transacting factors. The renal enlargement response can also be modified by endocrine hormones that can activate such genes directly and/or stimulate other adjunctive processes, like receptor expression for the regional binding of growth factors. Furthermore, renal enlargement is under negative feedback of inhibitory factors like TGF beta. It is possible, for example, that special genes exist which are only expressed to arrest enlargement. It has been further suggested that activation of the Na+/H+ antiporter is a common denominator in renal enlargement. Recent findings, however, indicate that the activation of this antiporter is not always necessary, and might rather be a parallel event rather than a key phenomena in tubular enlargement. G0/G1 transition of tubular cells seems to involve similar factors in tubular hypertrophy and hyperplasia. The factors which are responsible for the final determination of the enlargement pattern (hypertrophy vs. proliferation) are unknown. The separation between hypertrophy and hyperplasia, although suggested by striking differences in cellular regulation, may be somewhat artificial, since responses leading to tubular enlargement also exist in circumstances where hyperplasia and hypertrophy are combined events. Recently it has been proposed that growth factors stimulate gluconeogenesis in proximal tubular cells producing hyperplasia, whereas factors inhibiting gluconeogenesis might induce hypertrophy. Whether the common pathway message of this intriguing hypothesis is correct still requires further validation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1989

Novel cellular interactions and networks involving the intestinal immune system and its microenvironment.

The interactions we have described enable the intestine to respond appropriately to antigenic challenge in an effective and coordinated way. This is of vital importance when one considers the dual role of the intestine as a first line of defence against harmful microorganisms and as the route by which the animal obtains nutrition. Under normal circumstances, these interactions select for an appropriate cell phenotype by providing a network of interactions that contribute to intestinal homeostasis. If there is dysfunction of any component, then other cells will be affected. For example, if down-regulation of the mucosal immune response is not effective, damage to the epithelium, nerves and muscle may occur during an inflammatory response. Similarly, if the integrity of the epithelium is disrupted, damage to the elements of the mucosal immune system may occur. This model would suggest that these interactions must be considered if one wishes to adequately explain diseases such as IBD and design innovative therapeutic regimens. Future interdisciplinary research will shed light on the web of interactions occurring in the intestinal environment and provide a novel view of the respective contributions of the immune system and its local environment to cell differentiation, function and regulation.

Animals↗

PubMed2000

Functional disturbances in hemopoietic microenvironment in various forms of myelodysplastic syndrome.

We studied the ability of stromal sublayer of long-term bone marrow cultures and peripheral blood macrophages from patients with various forms of myelodysplastic syndrome to maintain the growth of normal granulocyte-macrophage colony-forming units in mixed cultures. There were changes in the hemopoietic microenvironment in these patients: decreased cellularity of the bone marrow and impaired formation of sublayers in long-term bone marrow cultures, production of growth factors, maintaining the growth of normal granulocyte-macrophage precursors by stromal cells. Dysfunction of macrophages in the stromal microenvironment was probably related to the presence of pathological macrophages./Abstract>

Bone Marrow↗

PubMed2001

Immortalized multipotential mesenchymal cells and the hematopoietic microenvironment.

In an attempt to analyze the cellular and molecular basis of the capacity of bone marrow stromal cells to support hematopoiesis in culture, we developed a series of murine stromal cell lines from a single long-term bone marrow culture (BMC). The cytokines produced by these cells were analyzed using immunohistochemical techniques, ribonuclease protection assays (RPA) and RT-PCR. We examined the capacity of these cloned cell lines to replace primary bone marrow-derived stromal cells in long-term bone marrow cultures (LT-BMC) and sought correlations between the capacity to support hematopoiesis in culture with the production of known cytokines. These immortalized lines replicate many of the functions of the hematopoietic microenvironment. They express cytokines known to play a role in hematopoiesis. All of the lines constitutively express mRNA for PBSF (SDF-1), macrophage colony-stimulating factor (M-CSF), stem cell factor (SCF), FLT-3, thrombopoietin (TPO), interleukin 7 (IL-7), leukemia inhibitory factor (LIF), tumor necrosis factor-beta (TNF-beta), and interferon-gamma (IFN-gamma). Most lines also express granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF. They vary in their expression of IL-6, tumor growth factor-beta1 (TGF-beta1), TGF-beta2, and TNF-alpha. Growing these lines in the presence of cytokines that influence hematopoiesis alters the levels of cytokine message. The most striking effects were produced by TNF-alpha. In addition to the cytokine mRNAs, the cell lines express factors associated with bone formation such as osteoblast-specific factor-2 (OSF-2) and bone morphogenetic protein-1 (BMP-1). They also express the neural cell-adhesion molecule neuropilin and neurotrophic factors including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Several of the lines can maintain hematopoiesis in culture, as measured by the continuous production of myeloid colony-forming cells (CFU-c), for months. This capacity to support hematopoiesis does not correlate with any pattern of cytokine expression. Several of these lines also support the growth of human hematopoietic cells, and human CFU-c can be detected in the cultures in which CD34(+) bone marrow cells (BMC) are cultured on murine stromal cells. No correlation between the production of any of the known cytokines and the ability to support murine hematopoiesis was detected. In addition, there was no correlation between the capacity to support murine hematopoiesis and the capacity to maintain human HSC. Despite repeated cloning, the lines remain heterogeneous and are capable of producing cells with the properties of fibroblasts, osteoblasts, adipocytes, and myoblasts. In addition to the cytokine mRNAs, the cell lines express factors associated with bone formation such as OSF-2 and BMP-1. They also express the neural cell-adhesion molecule neuropilin and neurotrophic factors including NGF and BDNF.

Animals↗

PubMed1987

Quantitative study of microvessel ultrastructure in human peritumoral brain tissue. Evidence for a blood-brain barrier defect.

The form and function of blood vessels are determined by the cells that constitute their microenvironment. Brain tissue around tumors contains varying numbers of tumor cells that could influence local capillaries to lose their blood-brain barrier (BBB), as they do in the tumor itself. Microvascular permeability cannot be measured directly in humans but can be inferred from a knowledge of vessel ultrastructure. The authors have examined the vascular ultrastructure associated with the BBB in human peritumoral brain tissue for evidence of BBB compromise and to correlate BBB features with the cellular components of the vessel microenvironment. Light microscopic examination of brain tissue samples in patients with primary brain tumors showed that the tissue lying beyond the visible edge of the tumor ranged from essentially normal to grossly infiltrated with tumor cells. Although some of the vessels were structurally normal, the microvessels as a group had elongated junctional clefts (unfused regions) and an increase in the density of endothelial vesicles. Furthermore, the cleft index (the percentage of the junctional profile that is unfused) varied directly with the local cell density. A subpopulation of vessels enveloped by a layer of tumor cells was grossly abnormal. However, vessels that were not immediately invested by tumor cells also showed some abnormalities. It is concluded that tumor cells infiltrating peritumoral brain tissue cause blood vessels to take on some of the structural characteristics of leaky vessels. Since direct contact is not required, and since the degree of abnormality correlates with the number of tumor cells in the environment, the authors suggest that this inductive influence is exerted over a distance and is dependent on the concentration of the inducing factors.

Adult↗

PubMed1987

Effect of cisplatin resistance on cellular radiation response.

Cisplatin-resistant tumors of the head and neck are generally resistant to irradiation. To determine whether the association between cisplatin (DDP) resistance and radiation resistance is a cellular phenomenon, we developed DDP-resistant Chinese hamster fibroblasts and studied their response to radiation. DDP resistance did not confer cross resistance to radiation. DDP-resistant cells did not demonstrate altered ability to repair sublethal or potentially lethal radiation damage. However, an isodose concentration of DDP did not inhibit repair of radiation damage in drug-resistant cells as readily as it did in drug-sensitive cells. The results suggest that cross resistance of tumors between DDP and radiation may be a result of the tumor microenvironment, rather than being a cellular phenomenon. Additionally, DDP may not inhibit the repair of radiation damage in DDP-resistant tumors.

Animals↗

PubMed2026

CARS1 as a Prognostic Biomarker and Candidate Therapeutic Vulnerability in Hepatocellular Carcinoma: Insights Into Tumor Progression and the Immune Microenvironment.

BACKGROUND: Cysteinyl-tRNA synthetase 1 (CARS1) has been included in ferroptosis-related prognostic signatures, but its clinicopathological relevance, cellular functions, and relationship with the immune microenvironment in hepatocellular carcinoma (HCC) remain incompletely characterized. METHODS: Transcriptomic and clinical data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset were integrated with corresponding data from an institutional HCC tissue cohort of 60 patients. CARS1 expression was evaluated by immunohistochemistry, and immune infiltration was examined using single-sample gene-set enrichment analysis (ssGSEA) and multiplex immunofluorescence, as well as by analyzing public single-cell datasets. The effects of CARS1 depletion were evaluated in MHCC97H and Hep3B cells using Cell Counting Kit-8 (CCK-8) assays, cell-cycle profiling, wound-healing assays, Transwell migration assays, western blotting, and erlotinib-sensitivity assays. RESULTS: CARS1 expression was elevated in HCC and was associated with adverse clinicopathological features and poor overall survival. Quantitative immunohistochemistry confirmed elevated CARS1 protein expression in tumor tissues. CARS1 depletion inhibited cell proliferation, altered cell-cycle distribution, impaired migration, and enhanced in vitro sensitivity to erlotinib. High CARS1 expression was also associated with increased infiltration of Th2-like immune cells. CONCLUSIONS: Elevated CARS1 expression is associated with an adverse biological and immune phenotype in HCC. These clinical, histopathological, and loss-of-function findings support further investigation of CARS1 as a prognostic marker and candidate therapeutic target in HCC, although additional mechanistic and in vivo validation is required.

Humans↗

PubMed1986

Cellular aspects of radiation leukemogenesis in C57 BL/Ka mice: alterations to thymic microenvironment and lymphopoiesis.

After a leukemogenic split dose course of irradiation, thymic nurse cells (TNCs) disappear. We have correlated this with the loss of an epithelial cell surface antigen (recognized by monoclonal antibody ER-TR3 and tentatively identified as Ia). In addition, epithelial cells have lost their capacity to interact with fetal thymocytes in vitro. Marrow grafting early after irradiation, that prevents the development of lymphomas, restores thymic nurse cells and thymocyte population. Such reconstitution and lymphoma prevention were not observed when marrow grafting was performed later (1 month after irradiation) during the preleukemic period.

Animals↗

PubMed1998

Immunocytokines: a promising approach to cancer immunotherapy.

Recombinant antibody-cytokine fusion proteins are immunocytokines that achieve high cytokine concentrations in the tumor microenvironment and thereby effectively stimulate cellular immune responses against malignancies. The activation and expansion of immune effector cells, such as CD8+ T lymphocytes, by interleukin-2 immunocytokines resulted in the eradication of established pulmonary and hepatic metastases of murine melanoma and colorectal carcinoma in syngeneic mouse models. These immunocytokines were equally effective in eliminating established bone marrow and liver metastases of murine neuroblastoma by activating natural killer cells. The effective eradication of metastases by immunocytokines resulted in significant prolongation in life span of mice over that of controls receiving equivalent mixtures of antibody and interleukin-2, which failed to reduce the growth of disseminated metastases. Proof of concept was established, indicating that immunocytokine-induced activation and expansion of immune effector cells in the tumor microenvironment can effectively eradicate established tumor metastases. This promising new approach to cancer immunotherapy may lead to clinical applications that improve treatment of cancer patients with minimal residual disease in an adjuvant setting.

Animals↗

PubMed2026

Multiomics analysis reveals that senescent CXCL16+ macrophages promote lung adenocarcinoma progression through TGF-β signalling.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer and remains a leading cause of cancer-related mortality worldwide. Although, immunotherapy has become a cornerstone of first-line treatment, only 20-30% of patients achieve a durable clinical benefit, largely because of the complexity and heterogeneity of the tumour immune microenvironment. Emerging evidence indicates that cellular senescence, particularly within immune cells, contributes to tumour progression by impairing antitumour immunity; however, its mechanistic role in LUAD remains incompletely understood. METHODS: We performed an integrative multiomics analysis incorporating genome-wide association studies (GWASs), bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics to characterize immune heterogeneity in LUAD. Cellular senescence was validated by performing staining for senescence-associated β-galactosidase and the canonical markers p16 and p21. SHAP analysis was applied to evaluate the contribution of CXCL16+ macrophages. Functional roles were assessed using coculture assays, in vitro and in vivo tumour models, orthotopic tumour implantation, and multiplex immunofluorescence staining of clinical specimens. RESULTS: A summary data-based on Mendelian randomization analysis integrating GWAS and TCGA data identified CXCL16 as a senescence-associated gene that is causally linked to the LUAD risk. Single-cell RNA sequencing revealed that CXCL16 is predominantly expressed in macrophages, and the pseudotime analysis together with β-galactosidase staining confirmed its association with macrophage senescence. Spatial transcriptomics and immunofluorescence staining showed the marked enrichment of CXCL16+ macrophages in LUAD tissues. The cell-cell communication analysis further revealed a strong association between the number of CXCL16+ macrophages and the activation of the TGF-β signalling pathway within the tumour microenvironment. Functionally, CXCL16+ macrophages promoted LUAD progression via TGF-β signalling, as validated in vitro and in subcutaneous and orthotopic tumour models. Molecular dynamics simulations additionally suggested that LUAD patients with high levels of CXCL16+ macrophage infiltration may exhibit increased sensitivity to bosutinib. CONCLUSIONS: CXCL16 promotes macrophage senescence, and senescent CXCL16+ macrophages drive LUAD progression through TGF-β signalling. These findings identify CXCL16+ macrophages as a biologically and therapeutically relevant immune cell population, highlighting a potential target for precision intervention in LUAD.

Humans↗