Unveiling LAIR1: a prognostic biomarker associated with gastric cancer progression and metastasis

Introduction

Gastric cancer (GC) continues to pose a significant worldwide health burden. Although diagnostic and therapeutic approaches have improved, morbidity and mortality rates remain unacceptably high (1). A key factor in its poor prognosis is the tendency for aggressive metastatic spread and the frequent emergence of resistance to treatment (2,3). Consequently, a deeper understanding of the molecular drivers of tumor invasion, metastasis, and therapeutic failure is urgently needed to enhance patient survival (4,5).

Recent investigations have highlighted a potential role for leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) in cancer biology, particularly within the context of immune modulation and the tumor microenvironment (6,7). LAIR1 is primarily known as an inhibitory receptor expressed on multiple immune cell subsets, such as T and B lymphocytes, natural killer cells, and monocytes. Its engagement by collagen and other matrix ligands transduces signals that suppress immune cell activation and anti-tumor effector responses (8,9). This immunosuppressive activity positions LAIR1 as a critical checkpoint in maintaining immune homeostasis but also as a potential contributor to immune evasion in cancer (10). Beyond its role on immune cells, emerging evidence suggests that LAIR1 can be expressed on certain tumor cells themselves, where it may contribute to cancer progression and metastasis through tumor-intrinsic pathways, an area that remains incompletely understood.

In this study, it was found that LAIR1 is highly expressed in GC tissues and, through bioinformatics analysis and examination of GC tissue samples, is closely associated with poor prognosis and adverse pathological features. The present study has demonstrated that LAIR1 over-expression promotes proliferation, invasion and migration in GC, a finding that has been fully validated in animal models. This finding underscores the potential of this pathway as a therapeutic target for GC. We present this article in accordance with the MDAR and ARRIVE reporting checklists (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0136/rc).

Methods

Tissue specimens

Tissue samples for immunohistochemistry (IHC) comprised 177 archival paraffin-embedded gastric carcinomas and 30 matched non-cancerous tissues (collected from the Department of Pathology between October 2020 and October 2021), along with 16 pairs of freshly resected GC and normal tissues from the Department of Gastrointestinal Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by The First Affiliated Hospital, Jiangxi Medical College, Nanchang University [approval No. (2023)CDYFYYLK(03-017)] and informed consent was obtained from all individual participants.

Bioinformatics analysis

Publicly available GC transcriptomic data were sourced from The Cancer Genome Atlas (TCGA) portal. Differential expression of LAIR1 and its clinicopathological correlations in GC were evaluated using R software (v4.1.0). Pan-cancer expression profiling of LAIR1 was conducted via the TIMER2 and GEPIA2 platforms. The prognostic significance of LAIR1 expression in GC was assessed using the Kaplan-Meier plotter and PanCanSurvPlot online tools.

Hematoxylin-eosin (H&E) and IHC

Conventional H&E staining was performed on paraffin sections for histological assessment. For IHC, sections underwent antigen retrieval, blocking, and overnight incubation at 4 ℃ with primary antibody, followed by appropriate horseradish peroxidase (HRP)-conjugated secondary antibody. Diaminobenzidine (DAB) was used as the chromogen, with hematoxylin counterstaining. Stained slides were examined under a bright-field microscope. All IHC scores were independently and blindly assessed by two associate chief physicians in pathology. In cases of significant discrepancies, a third associate chief physician was consulted for evaluation. To assess interobserver agreement, we calculated Cohen’s kappa coefficient, which yielded a value of 0.909, indicating excellent agreement between the two pathologists. A semi-quantitative scoring method was applied, integrating staining intensity and the percentage of positive cells. The final IHC score was calculated by multiplying these two values. Using X-tile software, the optimal cutoff value was identified as 10 (Figure S2D); samples were thus categorized into low-expression (score ≤9) and high-expression (score >9) groups.

Protein and RNA analysis

Protein samples were prepared using RIPA lysis buffer and subsequently analyzed by immunoblotting as reported previously (11). Total RNA was extracted, reverse-transcribed into cDNA, and quantified by quantitative real-time polymerase chain reaction (qRT-PCR), also following the established protocol (11). Details regarding the primary antibodies and gene-specific primers utilized in these assays are provided in Tables S1,S2, respectively.

Cell culture and transfection

Cell lines, including six human GC lines (MKN45, AGS, HGC27, MKN28, MGC803, and SGC7901) and the non-malignant gastric mucosal epithelial line GES-1, were acquired from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). They were cultured under standard conditions [RPMI-1640, 10% fetal bovine serum (FBS), 37 ℃, 5% CO₂], with identity [short tandem repeat (STR) analysis] and mycoplasma contamination routinely verified.

To modulate LAIR1 expression, lentiviral vectors carrying short hairpin RNA targeting LAIR1 (shLAIR1), a nontargeting scrambled negative control short hairpin RNA (shNC), or a LAIR1 overexpression cassette were constructed and supplied by Shanghai GeneChem Co., Ltd. (Shanghai, China). Following transduction, stable polyclonal populations were selected under puromycin pressure, and transfection efficiency was validated prior to subsequent functional assays. The detailed oligonucleotide sequences are listed in Table S3.

Cell proliferation assays [Cell Counting Kit-8 (CCK-8) and colony formation]

Proliferation was assessed via short- and long-term assays. Short-term viability was measured with a CCK-8 kit: transfected cells in 96-well plates were incubated with CCK-8 reagent for 1.5 h, and absorbance at 450 nm was recorded. For long-term clonogenic growth, cells were plated sparsely in six-well plates, cultured for 14 days, then fixed and stained with crystal violet; colonies of >50 cells were counted manually.

Cell migration and invasion assays (scratch wound and Transwell)

Cell migration and invasion were evaluated with scratch wound and Transwell-Matrigel assays, respectively. In the scratch assay, a linear wound was generated in a confluent monolayer using a sterile tip. Gap closure was monitored at 0 and 24 h under phase-contrast microscopy. For invasion assessment, cells were seeded into Matrigel-coated upper invasion chambers, with complete medium placed below to establish a chemoattractive gradient. Following 24 h of incubation, non-invading cells were cleared from the upper surface, while cells that migrated through the matrix to the lower membrane were fixed, stained with crystal violet, and counted microscopically. Each experiment was conducted in triplicate.

Animal models

Four-week-old female BALB/c-nude mice were purchased from Hangzhou Ziyuan Experimental Animal Technology Co., Ltd. [License No. SCXK (Zhe) 2019-0004]. After passing quarantine at the laboratory, they were randomly divided and acclimatized for 1 week in an SPF-grade environment. Experiments were performed under a project license (ethics No. CDYFY-IACUC-202304QR050) granted by the Animal Welfare and Ethics Committee of The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, in compliance with the national or institutional guidelines for the care and use of animals.

Subcutaneous tumor model

1×10⁷ cells/mL suspensions were prepared in culture medium and mixed with an equal volume of Matrigel. For each group (n=5), 200 µL was injected subcutaneously into the mouse flank. Once nodules were palpable, tumor dimensions were measured every 3 days, and volume was calculated as V = (L × W²)/2 (L: longest diameter; W: shortest). Following a 4-week observation period, mice were humanely sacrificed. The resulting tumors were carefully dissected, their mass recorded, and then immersion-fixed in 4% paraformaldehyde for subsequent histological and molecular examination.

Peritoneal metastasis model

Using an identical cell preparation protocol, a 200 µL suspension was administered via intraperitoneal injection to nude mice (n=5 per cohort). A blunt-needle technique was employed to minimize post-injection leakage. After 21 days, the animals were euthanized. The abdominal cavity was systematically inspected, and all visible metastatic nodules on the peritoneal surface and mesentery were enumerated, harvested, and placed in 4% paraformaldehyde fixative.

Lung metastasis model

To reduce the likelihood of vascular embolism, the cell suspension was mixed at a 1:2 ratio with Matrigel prior to injection. A volume of 200 µL was then slowly delivered into the tail vein of restrained nude mice (n=5 per group). Five weeks post-injection, the mice were sacrificed, and the lungs were surgically removed. The tissue was gently inflation-fixed with 4% paraformaldehyde to preserve architecture. Following standard paraffin embedding, serial sections were cut and stained with H&E to facilitate the identification and quantification of metastatic foci under microscopic examination.

Lymphatic metastasis model

Mice were anesthetized with isoflurane. Fifty µL of cell suspension was injected into the left hind footpad. Tumor growth and mouse condition were monitored every other day. After 5 weeks, mice were euthanized, and skin around the lower limb was carefully removed to expose popliteal and inguinal lymph nodes. Metastatic nodes were counted and analyzed statistically.

Statistical analysis

Data were analyzed with SPSS Statistics 25.0. Survival was analyzed by Kaplan-Meier plots, with comparisons made via the log-rank test. Quantitative data are mean ± standard error of the mean (SEM). Group differences were evaluated using a two-tailed Student’s t-test or one-way analysis of variance (ANOVA), with statistical significance defined as P<0.05.

Results

Bioinformatic analysis reveals that high LAIR1 expression is associated with poor prognosis in GC

We first analyzed LAIR1 expression across pan-cancer using the TIMER2 database, finding high LAIR1 expression in 9 tumor types and low expression in 5 others (Figure 1A). Analysis via the GEPIA2 database showed high expression in 11 tumor types and low expression in 3 (Figure S1A). TIMER2 corrects for tumor purity using RNA sequencing (RNA-seq) data, while GEPIA2 directly compares tumor vs. normal tissue expression; differing datasets incorporated by each platform account for the observed variations. Integrating results from both databases identified consistent high LAIR1 expression in stomach adenocarcinoma (STAD) compared to normal tissues.

Figure 1 Bioinformatic analysis of LAIR1 expression in pan-cancer and its prognostic value in GC. (A) LAIR1 expression across cancers from TIMER2. (B-D) Poor prognosis associated with high LAIR1 expression (probe 208071_s_at) in GC: (B) OS, (C) FPS, (D) PPS. (E-G) Poor prognosis associated with high LAIR1 expression (probe 210644_s_at) in GC: (E) OS, (F) FPS, (G) PPS. *, P<0.05; ***, P<0.001. CI, confidence interval; FPS, first progression survival; GC, gastric cancer; HR, hazard ratio; LAIR1, leukocyte-associated immunoglobulin-like receptor 1; OS, overall survival; PPS, post-progression survival; TPM, transcripts per million.

Focusing on GC, we evaluated the prognostic value of LAIR1. Kaplan-Meier Plotter analysis revealed that the LAIR1 probe 208071_s_at significantly correlated with poor prognosis in overall survival [OS, P=0.001, hazard ratio (HR) =1.34, Figure 1B], first progression survival (FPS, P=0.003, HR =1.37, Figure 1C), and post-progression survival (PPS, P=2e−08, HR =1.93, Figure 1D). Similarly, probe 210644_s_at correlated with poor OS (P<0.001, HR =1.46, Figure 1E), FPS (P=0.009, HR =1.37, Figure 1F), and PPS (P=8.5e−06, HR =1.74, Figure 1G). Further analysis using the PanCanSurvPlot database across multiple datasets, platforms, and therapies confirmed LAIR1’s association with poor GC prognosis in most cohorts, except for dataset GSE26253 (P=0.18, HR =0.791, Table S4). Collectively, these multi-database analyses demonstrate that LAIR1 expression is associated with unfavorable prognosis in GC.

Expression of LAIR1 in GC tissues and its clinicopathological correlations

To investigate factors underlying LAIR1’s prognostic impact, we analyzed clinicopathological correlations in the TCGA GC dataset. LAIR1 expression showed no significant association with gender (P=0.82, Figure S1B) or age (P=0.68, Figure S1C). However, it strongly correlated with tumor differentiation grade (G1 vs. G3, P=0.043; G2 vs. G3, P=6.4e−11, Figure S1D) and T stage (T1 vs. T2/T3/T4, all P<0.001, Figure S1E). While no significant differences were found across N stages (all P>0.05), median expression levels showed an increasing trend from N0 to N3 (Figure S1F), potentially due to limited sample size. LAIR1 expression differed significantly between stage I vs. II (P=0.001) and stage I vs. III (P=0.001), but not between stage I vs. IV (P=0.10, Figure S1G), possibly also related to small stage IV sample size.

To validate these findings, we performed IHC on 177 GC patient samples. LAIR1 was primarily expressed in the cytoplasm and was significantly higher in tumor tissues compared to adjacent normal tissues (Figure 2A), consistent with bioinformatic results. Furthermore, to provide objective and reproducible evidence, we systematically quantified LAIR1 staining intensity across multiple regions of interest (ROIs) per sample, revealing a significant increase in tumor tissues (Figure S2A). The frequency distribution of LAIR1 IHC scores across all 177 samples is shown in Figure S2B, illustrating the range, central tendency, and spread of the scores. IHC scoring revealed significant correlations between high LAIR1 expression and poor differentiation, advanced T stage, tumor-node-metastasis (TNM) stage, larger tumor size, lymph node metastasis, and vascular invasion (all P<0.05), but not with age or gender (Table 1). Survival analysis confirmed that high LAIR1 expression correlated with worse OS and PFS (both P<0.001, Figure 2B,2C). These IHC results validate the bioinformatic analysis, indicating that high LAIR1 expression correlates with aggressive clinicopathological features and poor prognosis, supporting its potential as a reliable biomarker implicated in GC invasion and metastasis.

Figure 2 Expression and prognostic analysis of LAIR1 in GC. (A) Representative images showing low LAIR1 expression in normal gastric tissue and high expression in GC tissue. Negative staining (IHC scores 1–2), weak staining (IHC scores 3–4), moderate staining (IHC scores 6–9), and strong staining (IHC scores 12). (B) OS based on LAIR1 expression status. (C) PFS based on LAIR1 expression status. (D) LAIR1 protein expression in 16 paired GC tissues (N: adjacent normal; T: tumor). (E) LAIR1 mRNA levels in the same 16 paired tissues. ****, P<0.0001. GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GC, gastric cancer; IHC, immunohistochemistry; LAIR1, leukocyte-associated immunoglobulin-like receptor 1; mRNA, messenger RNA; OS, overall survival; PFS, progression-free survival.

We further validated LAIR1 expression in 16 paired fresh GC tissues. Western blot analysis revealed significantly higher LAIR1 protein levels in tumor tissues compared with adjacent normal tissues (P<0.001, Figure 2D,2E). Similarly, qRT-PCR confirmed a significant upregulation of LAIR1 messenger RNA (mRNA) levels in tumor tissues (P<0.001, Figure S2C). These results are consistent with the prior bioinformatic and IHC findings.

Effect of LAIR1 on GC cell proliferation

LAIR1 protein expression was evaluated in GC cell lines (HGC27, MKN28, MKN45, MGC803, AGS, and SGC7901). It was highly expressed in most lines, highest in MGC803 (P<0.001, Figure 3A,3B), and relatively low in MKN45 (not significantly different from GES1, P>0.05, Figure 3A,3B). Therefore, MGC803 (for knockdown) and MKN45 (for overexpression) were selected for further study.

Figure 3 LAIR1 expression and its impact on GC cell proliferation. (A) LAIR1 protein levels in various GC cell lines. (B) Statistical analysis of LAIR1 expression across cell lines. (C) Validation of LAIR1 knockdown efficiency via lentivirus in MGC803 cells. (D) Validation of LAIR1 overexpression efficiency in MKN45 cells. (E) Effect of LAIR1 knockdown on cell viability (CCK-8). (F) Effect of LAIR1 overexpression on cell viability (CCK-8). (G) Colony formation after LAIR1 knockdown in MGC803 cells (crystal violet staining). (H) Colony formation after LAIR1 overexpression in MKN45 cells (crystal violet staining). **, P<0.01; ***, P<0.001; ****, P<0.0001; ns, not significant. CCK-8, Cell Counting Kit-8; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GC, gastric cancer; LAIR1, leukocyte-associated immunoglobulin-like receptor 1; NC, negative control; sh-1, shLAIR1-1; sh-2, shLAIR1-2; shLAIR1, short hairpin RNA targeting LAIR1.

Stable LAIR1-knockdown (shLAIR1-1 and shLAIR1-2) MGC803 cells and LAIR1-overexpressing MKN45 cells were generated (Figure 3C,3D). CCK-8 assays showed that knockdown significantly decreased proliferation (P<0.001, Figure 3E), while overexpression increased it (P<0.001, Figure 3F). Colony formation assays yielded consistent results: knockdown reduced colony numbers (P<0.001, Figure 3G), and overexpression increased them (P<0.001, Figure 3H). These in vitro experiments demonstrate that LAIR1 promotes GC cell proliferation.

Effect of LAIR1 on GC cell invasion and migration

Given LAIR1’s correlation with invasive features (T stage, lymph node/vascular invasion), we investigated its role in invasion and migration. Wound healing assays showed that LAIR1 knockdown reduced healing capacity (P<0.001, Figure 4A), while overexpression enhanced it (P<0.001, Figure 4B). Transwell invasion/migration assays confirmed that knockdown decreased invasive capacity (P<0.001, Figure 4C), and overexpression increased it (P<0.001, Figure 4D).

Figure 4 Effect of LAIR1 on GC cell migration and invasion. (A) Scratch wound assay in LAIR1-knockdown MGC803 cells. (B) Scratch wound assay in LAIR1-overexpressing MKN45 cells. (C) Transwell invasion assay in LAIR1-knockdown MGC803 cells (crystal violet staining). (D) Transwell invasion assay in LAIR1-overexpressing MKN45 cells (crystal violet staining). ***, P<0.001; ****, P<0.0001. GC, gastric cancer; LAIR1, leukocyte-associated immunoglobulin-like receptor 1; NC, negative control; sh-1, shLAIR1-1; sh-2, shLAIR1-2; shLAIR1, short hairpin RNA targeting LAIR1.

Effect of LAIR1 on GC cell tumorigenesis in nude mice

Subcutaneous xenograft models were established. Tumors in the negative control (NC) group were significantly larger (Figure 5A), grew faster (P<0.001, Figure 5B), and were heavier (P<0.01, Figure 5C) than those in the shLAIR1 group. IHC of xenograft tissues confirmed higher LAIR1 expression in the NC group (P<0.01, Figure 5D,5E). The proliferation marker Ki-67 showed a concordant expression pattern (higher in NC, P<0.01, Figure 5D,5F). These in vivo results confirm that LAIR1 promotes GC proliferation.

Figure 5 Effect of LAIR1 knockdown on subcutaneous tumor growth in nude mice. (A) Tumorigenesis in nude mice following LAIR1 downregulation. (B,C) Tumor progression: significant differences in subcutaneous tumor growth curves (B) and final tumor weights (C). (D) IHC scores for LAIR1 and Ki-67. (E) Representative IHC images for LAIR1. (F) Representative IHC images for Ki-67. **, P<0.01; ****, P<0.0001. IHC, immunohistochemistry; LAIR1, leukocyte-associated immunoglobulin-like receptor 1; NC, negative control; shLAIR1, short hairpin RNA targeting LAIR1.

Effect of LAIR1 on peritoneal metastasis in nude mice

In a peritoneal dissemination model, the shLAIR1 group developed significantly fewer metastatic nodules than the NC group (P<0.001, Figure 6A,6B). IHC of nodules revealed higher LAIR1 expression in the NC group (P<0.05, Figure 6C,6D). The NC group also exhibited higher expression of the epithelial-mesenchymal transition (EMT) regulator Snail1 (P<0.05, Figure 6C,6E), higher N-cadherin (P<0.05, Figure 6C,6F), and lower E-cadherin (P<0.05, Figure 6C,6G). These results indicate that LAIR1 promotes peritoneal metastasis, potentially via regulating EMT.

Figure 6 Effect of LAIR1 knockdown on peritoneal metastasis in nude mice. (A) Representative images of peritoneal metastatic nodules. (B) The number of nodules in the peritoneal metastases of nude mice exhibited significant variations. (C) IHC scores for LAIR1, Snail1, N-cadherin, and E-cadherin. (D-G) Representative IHC images for LAIR1 (D), Snail1 (E), N-cadherin (F), and E-cadherin (G). *, P<0.05; **, P<0.01; ****, P<0.0001. IHC, immunohistochemistry; LAIR1, leukocyte-associated immunoglobulin-like receptor 1; NC, negative control; shLAIR1, short hairpin RNA targeting LAIR1.

Effect of LAIR1 knockdown on lung and lymphatic metastasis in nude mice

To explore links to hematogenous and lymphatic spread, lung and lymphatic metastasis models were established. The shLAIR1 group showed significantly fewer lung metastatic nodules (P<0.001, Figure 7A-7C) and fewer lymph node metastases in inguinal/popliteal regions (P<0.001, Figure 7D,7E) compared to the NC group. This confirms that LAIR1 promotes both hematogenous and lymphatic metastasis in GC.

Figure 7 Effect of LAIR1 knockdown on lung and lymph node metastasis in nude mice. (A) Gross view of lung metastasis. (B) Lung metastatic nodules visualized by H&E staining. (C) Quantitative analysis of metastatic lung nodules. (D) Gross view of lymph node metastasis. (E) Quantitative analysis of metastatic lymph nodes. **, P<0.01; ****, P<0.0001. H&E, hematoxylin-eosin; LAIR1, leukocyte-associated immunoglobulin-like receptor 1; NC, negative control; shLAIR1, short hairpin RNA targeting LAIR1.

Discussion

This study, through systematic bioinformatic analysis, clinical sample validation, and in-depth in vitro and in vivo functional experiments, provides the first comprehensive elucidation of the oncogenic role of LAIR1 in GC. Our consistent data demonstrate that LAIR1 is significantly overexpressed in GC. Its expression level is closely associated with poor patient prognosis and multiple aggressive clinicopathological features, such as poor differentiation, advanced TNM stage, lymph node metastasis, and vascular invasion. This suggests that LAIR1 is not only a potential prognostic biomarker for GC but may also be directly involved in malignant progression.

Initial bioinformatic evaluation indicated that LAIR1 is frequently upregulated in various malignancies, consistent with prior pan-cancer studies (12). Within GC datasets, elevated LAIR1 expression robustly predicted inferior patient survival, mirroring its prognostic significance in carcinomas of the lung, breast, and liver (13-15). This clinical association was confirmed in our patient cohort, where high LAIR1 levels were linked to aggressive disease characteristics such as advanced T stage, lymph node involvement, and vascular invasion, consistent with the findings from a prior transcriptomic study that identified LAIR1 as one of the differentially expressed genes between histological subtypes in GC (16). Of particular functional significance, genetic ablation of LAIR1 attenuated the migratory, invasive, and metastatic potential of GC cells in vivo, impacting dissemination through peritoneal, hematogenous, and lymphatic routes. Conversely, exogenous LAIR1 expression potentiated these aggressive phenotypes. When integrated with prior evidence, these observations substantiate that LAIR1 functions as an active molecular driver of GC progression.

To probe the mechanistic basis of LAIR1-driven metastasis, we examined its influence on the EMT, a canonical pathway enabling cancer cell invasion and spread (17,18). Evidence from in vivo peritoneal metastasis models revealed that LAIR1 suppression triggered a molecular shift toward a more epithelial state. This was characterized by reduced levels of the EMT master regulator Snail1, decreased expression of N-cadherin, and a concomitant rise E-cadherin. This coordinated reversal of EMT markers implies that LAIR1 facilitates GC metastasis, in part, by initiating or maintaining the EMT program. Snail1 is a well-established transcriptional repressor of E-cadherin and a potent EMT inducer in multiple cancers (19,20). Our results place LAIR1 upstream of this critical regulator in GC. Although LAIR1 is traditionally characterized as an immune-inhibitory receptor within the tumor microenvironment, recent work highlights its direct tumor-cell-autonomous functions. For example, LAIR1 has been reported to drive proliferation and metastasis in osteosarcoma and hepatocellular carcinoma through EMT activation (21,22). Our study extends this concept to GC and identifies EMT as a key mechanistic conduit for LAIR1’s pro-metastatic effects.

A notable strength of this study is the validation of LAIR1’s role across multiple, clinically pertinent metastatic pathways. Peritoneal dissemination represents the most frequent and lethal form of GC metastasis, responsible for a high proportion of end-stage cases and presenting a major therapeutic hurdle (23,24). Our demonstration that LAIR1 knockdown profoundly reduces peritoneal tumor burden offers a direct preclinical foundation for targeting LAIR1 to address this clinical challenge. Moreover, the observed inhibition of both hematogenous and lymphatic metastases underscores LAIR1’s broad involvement in facilitating tumor spread through distinct anatomical routes. As a cell surface receptor harboring immunoreceptor tyrosine-based inhibitory motifs (ITIMs), LAIR1 represents a tractable therapeutic target (25,26). The development of monoclonal antibodies or small-molecule inhibitors against LAIR1 could potentially attenuate metastatic progression, possibly in combination with immunological therapy (27). This approach is supported by prior studies demonstrating that LAIR1 blockade—via antibody treatment, genetic deletion, or engineered constructs such as LAIR-2 fusion proteins—can remodel the tumor immune microenvironment, enhance antitumor immunity, and improve therapeutic efficacy in preclinical models (28-30). Specifically, LAIR1 inhibition has been shown to reduce M2-like tumor-associated macrophages, reshape collagen architecture, and facilitate effective tumor-T cell interactions, underscoring the translational potential of targeting this pathway (28-30).

While our research concentrates on the tumor-intrinsic, pro-metastatic functions of LAIR1, its established role as an immune checkpoint receptor suggests a broader, integrated hypothesis (31). High LAIR1 expression on cancer cells may not only propel EMT but also foster an immunosuppressive microenvironment via ligand engagement, potentially blunting anti-tumor immune responses (32,33). This dual capacity—enhancing cellular motility while simultaneously evading immune detection—could render LAIR1 a particularly potent oncogenic driver (34,35). This interplay warrants future investigation. Additionally, although our EMT findings are supportive, the upstream signals controlling LAIR1 expression in GC and its precise downstream signaling cascades remain to be fully delineated.

We acknowledge the limitations of our work. The detailed molecular events upstream and downstream of LAIR1 in the regulation of EMT are not yet fully resolved. Furthermore, given its immunoregulatory function, the role of LAIR1 within the GC tumor microenvironment—particularly its crosstalk with tumor-infiltrating immune cells—remains an intriguing and unexplored area that may be integral to its tumor-promoting activity.

Conclusions

In conclusion, we have systematically identified and validated LAIR1 as a key promoter of invasion and metastasis in GC. Its overexpression correlates with advanced disease and poor survival, and functional studies demonstrate its role in promoting proliferation, EMT, and multi-organ dissemination. These findings nominate LAIR1 as a promising prognostic biomarker and a compelling novel therapeutic target for intervening in the metastatic process of GC, addressing a critical unmet clinical need. Future research will focus on deciphering the downstream signaling network mediated by LAIR1 and its role within the tumor immune microenvironment.

Acknowledgments

The authors greatly thank Yi Tu and Yi Cao for their support. The authors would like to thank Zongfeng Feng and Qingwen Zeng for their valuable help.

Footnote

Reporting Checklist: The authors have completed the MDAR and ARRIVE reporting checklists. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0136/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0136/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0136/prf

Funding: This study was supported by the National Natural Science Foundation of China (No. 82103165), Jiangxi Provincial Health Technology Project (No. 202310020), The First Affiliated Hospital of Nanchang University Young Talent Research and Cultivation Project (No. YFYPY202272), the Science and Technology Project of Jiangxi Health Commission (No. 202410191), the Science and Technology Project of Jiangxi Provincial Department of Education (No. GJJ200225), and the “Talent 555 Project” of Jiangxi Province, China (No. ).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0136/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by The First Affiliated Hospital, Jiangxi Medical College, Nanchang University [approval No. (2023)CDYFYYLK(03-017)] and informed consent was obtained from all individual participants. Animal experiments were performed under a project license (ethics No. CDYFY-IACUC-202304QR050) granted by the Animal Welfare and Ethics Committee of The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, in compliance with the national and institutional guidelines for the care and use of animals.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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