KLRB1 gene in tumor immune regulation and disease prognosis: a multidimensional role review

Abstract

The CD161 protein encoded by the killer cell lectin-like receptor subfamily B member 1 (KLRB1) gene is a key immunoregulatory molecule, primarily expressed in natural killer (NK) cells and specific T cell subsets, playing a significant role in tumors and various immune-related diseases. With the application of multi-omics big data and single-cell sequencing technologies, the mechanisms by which KLRB1 functions in tumorigenesis, progression, and immune microenvironment regulation are becoming increasingly clear. This paper elucidates the mechanism by which KLRB1 mediates immune activation and immune evasion through the regulation of downstream signaling pathways, its multifaceted roles within the tumor microenvironment (TME), and explores its function in immunotherapy. This article systematically reviews the expression characteristics of KLRB1 in various cancers such as breast cancer, hepatocellular carcinoma, and colorectal cancer, and analyzes the correlation between its expression levels and patient prognosis as well as immune cell infiltration in the TME. Beyond the field of oncology, the important role of KLRB1 in other immune-related diseases such as sepsis, psoriasis, and osteoporosis is also increasingly prominent. In-depth research on KLRB1 will provide new insights for future diagnostic and therapeutic strategies for the aforementioned diseases.

Introduction

Immunotherapy is developing rapidly. Although immune checkpoint inhibitors have shown significant efficacy in various cancers, only a small number of patients can achieve durable responses, while most patients exhibit primary or acquired resistance [1]. There is an urgent need to study new immune checkpoints, and the killer cell lectin-like receptor subfamily B member 1 (KLRB1) gene is gradually coming into research focus [2, 3].

The CD161 molecule encoded by the KLRB1 gene is an important immunomodulatory receptor that is heterogeneously expressed in various immune cells. It profoundly influences the activation, differentiation, and function of cytotoxic lymphocytes and participates in regulating immune responses, tumorigenesis and development, and other immune-related disease processes [4–6]. Its function bridges innate immunity and adaptive immunity, and it is expressed on Mucosal‑Associated Invariant T (MAIT) cells, Innate Lymphoid Cells (ILCs), and T cell subsets, coordinating different immune cells. CD161 has dual functions: as a co-stimulatory molecule, it promotes the antitumor or anti-infection activity of T cells, such as synergizing with Lectin-like transcript 1 (LLT1) to enhance T cell receptor signaling and promote interferon-γ (IFN-γ) secretion [7]; on the other hand, its binding with LLT1 can also inhibit the cytotoxic activity of NK cells, regulating immune responses to prevent excessive activation [8, 9]. This dual functionality makes KLRB1 a key checkpoint molecule in maintaining the balance between immune activation and tolerance. Its molecular mechanism involves the phosphorylation of atypical tyrosine residues in the cytoplasmic tail of KLRB1, which recruits phosphatases such as Src homology region 2 domain-containing phosphatase-1 (SHP-1), thereby inhibiting signaling pathways such as nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) to block immune cell activation and exert negative immunoregulatory effects [10].

Studies have shown that the expression of KLRB1 in tumors exhibits differential characteristics, being downregulated in most malignant tumors but upregulated in specific cancers such as kidney cancer and testicular germ cell tumors [11]. Furthermore, the expression of KLRB1 in various malignant tumors and autoimmune diseases shows dynamic changes, suggesting its potential as a biomarker for disease prognosis and treatment response. For example, in patients with rheumatoid arthritis (RA), the frequency of KLRB1 + CD4+ T cells is positively correlated with the disease activity index. After effective treatment, the frequency of KLRB1 + Th17 cells in the peripheral blood of patients significantly decreases [12]. To elucidate the complex role of KLRB1 in various tumors and immune diseases, there is an urgent need for systematic and multi-dimensional review studies. Utilizing multi-omics databases and integrating recent bioinformatic analysis results can help clarify the pathways through which KLRB1 influences immune regulation and disease pathogenesis. We aim to provide a comprehensive framework to promote the development of precision medicine strategies targeting KLRB1-related pathways.

Expression characteristics of KLRB1 and CLEC2D

Expression distribution and function of the protein encoded by KLRB1

KLRB1 is located on band 12p13.31 of human chromosome 12 and encodes the CD161 protein. It is a type II transmembrane glycoprotein characterized by a C-type lectin-like domain, belonging to the C-type lectin receptor family [4]. It is primarily expressed in immune cells such as NK cells, γδ T cells, natural killer T (NKT) cells, and certain conventional T cell subsets (including CD8 + and CD4 + T lymphocytes) [13]. The aforementioned expression pattern highlights the role of CD161 in innate and adaptive immune responses, and it is crucial for maintaining the balance between immune activation and tolerance by regulating immune cell activity [14, 15]. Existing research confirms the importance of CD161 in immune cell markers and diseases. For example, the expression of CD161 can serve as a marker for T cell subsets with specific functions (such as the Th17 subset) [16] and is closely associated with various pathological conditions, including cancer, infectious diseases, and autoimmune diseases. Furthermore, the functional properties of CD161 depend on the cellular microenvironment and its interactions with ligands, enabling it to act as either an inhibitory or activating receptor, thereby regulating immune responses through signal transduction pathways. It can recognize ligands such as LLT1 (also known as CLEC2D) [17], which are widely expressed in various cell types, such as infected or transformed cells. The CD161-LLT1 axis plays a significant role in regulating immune responses against viral infections, tumorigenesis, and autoimmune diseases [18].

Upregulation and downregulation of KLRB1 expression in immune cells

Cytokines may upregulate or maintain CD161 under short-term stimulation. Taking human peripheral blood NK cells as an example, Interleukin‑12 (IL-12) can promote the transcription and messenger RNA (mRNA) accumulation of CD161 and upregulate its surface expression [19, 20]. However, the reasons for the downregulation of KLRB1 expression can be roughly divided into three categories. First, long-term stimulation of T cell receptor (TCR) signals leads to the downregulation of CD161 expression. When these CD4 + T cells with high CD161 expression are stimulated by TCR signals (such as antigen presentation or anti-CD3/CD28 antibody stimulation), the expression of CD161 significantly decreases with increasing stimulation intensity. Studies have shown that in in vitro cultured T cells, as stimulation intensity and duration increase, surface CD161 molecules undergo endocytosis or intracellular transport, resulting in a reduced proportion of positive cells detected by flow cytometry [21]. The proliferation process of immune cells is also accompanied by the downregulation of CD161 expression. After TCR activation of MAIT cells, as the cells proliferate, the expression of surface CD161 molecules linearly declines. Research indicates that the extent of reduction in CD161 expression levels is positively correlated with the number of cell divisions [21, 22]. Under specific antigen stimulation, CD161 expression also shows a downward trend. For example, MAIT cells may exhibit a “functionally exhausted” phenotype under long-term antigen stimulation. At this time, CD161 expression levels decrease, accompanied by the upregulation of inhibitory receptors such as programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) [23]. In summary, the expression of KLRB1 exhibits dynamic changes under the activation states of different immune cells.

Analysis of CLEC2D expression differences in immune cell subsets

Under physiological homeostatic conditions, the expression of LLT1 is primarily restricted to subsets of B cells, such as centroblasts and centrocytes located within the germinal centers of lymph nodes or tonsils [8]. The upregulation of LLT1 in B cells is mediated by the co-crosslinking of the B cell receptor and CD40, as well as stimulation through Toll-like receptor signaling [18]. Upon TCR stimulation, LLT1 expression is upregulated in T cells [18, 24]. For NK cells, the induced expression of this molecule is mediated by the crosslinking of TCR with CD16. Immature dendritic cells typically do not express LLT1, whereas monocyte-derived dendritic cells and plasmacytoid dendritic cells can be induced to express LLT1 following TCR-related stimulation [18, 24, 25]. In fetal tissues, resident macrophages in the intestine and bone tissues can express LLT1 [26, 27] (Table 1).

Table 1.

The differences in expression and activation of CLEC2D among different immune cell subsets

Immune cell types	Subtypes	CLEC2D expression status	Activation signal	References
B cells	CB/CC	+	BCL6 TLR	[8] [24]
	Activated B cells	+	BCR-CD40-TLR TLR	[18]
T cells	Activated T cells	+	TCR	[18, 24]
NK cells	Activated NK cells	+	TCR-CD16	[18, 24]
DC	imDC	−	NA	[18]
	pDC	+	TLR	[18, 24, 25]
	Mo-DC	+	TLR	[24, 25]
Macrophages	TAM	+	NA	[26]
	Macrophages (Intestinal)	+	NA	[26]
	Macrophages (bone)	+	NA	[27]

Note: CB/CC: centroblast/centrocyte; DC: Dendritic Cells; imDC: immature Dendritic Cells; pDC: plasmacytoid Dendritic Cells; Mo-DC: Monocyte-derived Dendritic Cells; TAM: Tumor-associated macrophages; NA: Not applicable

Expression characteristics and prognostic value of KLRB1 in various tumors

Expression characteristics of KLRB1 in various tumors

In addition to classical immune receptors, metabolic enzymes such as Adenylosuccinate lyase (ADSL) have been established as important pan-cancer immune biomarkers, highlighting the complexity of the tumor immune regulatory network. KLRB1, the focus of this review, represents another class of key immunomodulatory molecules [28]. Large-scale pan-cancer analyses integrating public database resources such as TCGA, GEO, CCLE, GTEx, and HPA systematically reveal the differential expression patterns of KLRB1 across various cancers. In the vast majority of malignant tumor tissues, including breast cancer (BC), lung adenocarcinoma (LUAD), esophageal squamous cell carcinoma (ESCC), and colorectal cancer (CRC), the expression of this gene shows a downregulation trend [11]. However, in certain specific cancer types, such as kidney cancer and testicular germ cell tumors (TGCT) [29, 30], KLRB1 expression is relatively upregulated, suggesting that its expression regulation may be tissue- or tumor-type-specific and play different roles in tumorigenesis and development. In-depth analysis indicates that high expression of KLRB1 is primarily localized to various immune cells infiltrating the tumor tissue (such as CD8 + T cells, CD4 + T cells, dendritic cells, macrophages, etc.), while the vast majority of tumor epithelial cells themselves typically do not express KLRB1 or exhibit extremely low expression levels. There is a positive correlation between KLRB1 expression levels and the degree of immune cell infiltration, highlighting its role in regulating anti-tumor immunity [29]. In BC, although KLRB1 expression is generally downregulated compared to normal tissues, its higher expression levels within tumor tissues are positively correlated with increased infiltration of macrophages and T cells [31, 32]. A review on testicular germ cell tumors clearly states that seminomas typically exhibit significant lymphocyte infiltration histologically, with densely distributed, deeply stained lymphocytes visible microscopically between tumor cells. The dense immune cell infiltration may even obscure the tumor cells [33]. This may be the reason for the upregulation of KLRB1 expression in TGCT. In summary, high expression of KLRB1 detected in tumor tissues often indicates an “immune-hot” microenvironment, characterized by more active and abundant immune cell infiltration and aggregation in that area. Consistent with this, tumor purity is negatively correlated with KLRB1 expression: as KLRB1 expression levels increase, the “purity” of the tumor tissue decreases, meaning a lower proportion of cancer cells and a higher proportion of immune cells. Furthermore, KLRB1 expression is also associated with immune genomic features such as tumor mutational burden and microsatellite instability (MSI) [11], further reinforcing its role as a marker of the immune microenvironment.

Association of KLRB1 expression with pan-cancer immune infiltration

KLRB1 exhibits significant cellular heterogeneity and dynamic expression characteristics across various immune cell populations and disease contexts. In hepatocellular carcinoma (HCC), single-cell analysis has revealed elevated KLRB1 expression in tissue-resident NK cells and T cells, which co-express immune activation markers. For example, the co-expression of KLRB1 with Interleukin‑7 receptor (IL-7R) enhances the expression of Interleukin‑2 (IL-2), tumor necrosis factor-α (TNF-α), and perforin, thereby sustaining T cell proliferation and highlighting the role of KLRB1 in local immune surveillance and activation in HCC [34]. Conversely, studies have indicated that the interaction between KLRB1 and its ligand LLT1 transmits inhibitory signals to immune cells. For instance, KLRB1 is highly expressed on some “exhausted” or functionally impaired T cells. Research on recurrent liver cancer found that CD8 + T cells overexpressing KLRB1 exhibited lower intrinsic cytotoxic activity. Similarly, in BC, single-cell datasets and computational deconvolution methods (such as CIBERSORT) show that KLRB1 expression is closely associated with macrophage infiltration and other immune cell subsets. Particularly in triple-negative breast cancer (TNBC) tissues, a higher degree of cytotoxic T cell infiltration is often observed, suggesting that KLRB1 is involved in shaping the tumor immune microenvironment [31, 32]. In CRC, scRNA-seq data identified KLRB1 expression in specific T cell subsets, including exhausted and regulatory T cells. Another study further supports this view: in CRC patients who do not respond to PD-1 therapy, KLRB1 expression in T cells is higher and primarily enriched in exhausted CD8 + T cells. Further research indicates that KLRB1 expression levels are highly correlated with MSI status. In MSI-H (high microsatellite instability) colorectal cancer, KLRB1 is typically highly expressed. In ESCC, immune cell infiltration differs significantly between the tumor interior and tumor margin, and the spatial heterogeneity across different subregions remains unclear [35]. In LUAD, although the TME is infiltrated by a large number of immune cells, such as CD8-positive T cells and natural killer cells [36], there is also significant immunosuppression, particularly targeting CD8-positive T cells [37, 38]. The proportion of KLRB1 + CD8+ T cells in advanced LUAD is significantly lower than in early stages [39]. KLRB1 expression levels in cancer tissues of M1 stage patients are significantly downregulated compared to M0 stage [39]. Similarly, in clear cell renal cell carcinoma, despite the presence of a large number of tumor-infiltrating T lymphocytes [40], immune escape is prone to occur. The underlying mechanism may involve cancer cells producing cytokines such as Interleukin‑10 (IL-10), which can inhibit immune cell activation and promote Tregs differentiation. Tregs suppress the activity of effector T cells and promote tumor growth [41]. In testicular germ cell tumors, the infiltration level of CD4 + T cells is higher than that of CD8 + T cells [29, 42]. In glioma, single-cell analysis reveals that KLRB1 can serve as a marker for tumor-infiltrating T cells; these cells exhibit inhibitory receptor functions, suggesting that high KLRB1 expression may be associated with poor prognosis [43]. Further research found that Tregs infiltration is positively correlated with glioma grade, while CD8 + T cell infiltration is negatively correlated with glioma grade [44]. These findings collectively emphasize that KLRB1 expression is not static but varies depending on immune cell type, activation status, and disease state. As shown in Table 2.

Table 2.

KLRB1 expression, prognostic significance, and associated immune infiltration characteristics

Tumor type	Expression levels	Prognosis	Immune infiltration characteristics	References
Hepatocellular carcinoma (HCC)	The expression of KLRB1 in tumor tissue is significantly lower than that in normal tissue	Higher expression of KLRB1 tends to indicate a better prognosis	A. In CD8 + PD-1 + CD161+ T cell infiltration into the TME, the co-expression of CD161 and IL-7R enhances the expression of IL-2, TNF-α, and perforin, maintaining T cell proliferation B. In recurrent HCC, CD8 + T cells overexpressing KLRB1 are in a state of intrinsically low cytotoxicity	[34, 45, 46]
Breast cancer (BC)	A. Expression levels were significantly lower than those in normal breast tissue B. Decreased expression of KLRB1 is associated with age, T staging, pathological stage, and HER2 positivity	Patients with higher expression of KLRB1 have a longer survival period	In TNBC samples with high expression of KLRB1, there is often accompanied by more infiltration of cytotoxic T-lymphocytes	[11, 31, 32, 49]
Colorectal cancer (CRC)	A. Compared to normal tissues, the messenger RNA level of KLRB1 is decreased B. CD161 protein is significantly expressed in immune cells of colon cancer tumor tissue. C. In MSI-H colorectal cancer, KLRB1 is typically highly expressed	High expression of KLRB1 is often associated with better survival outcomes	In patients who do not respond to PD-1 therapy, the abundance of KLRB1⁺ T cells is higher	[47]
Esophageal squamous cell carcinoma (ESCC)	The expression level in ESCC is significantly lower than that in the corresponding normal esophageal tissue	Knockdown of KLRB1 inhibits the growth of human ESCC cells and prolongs survival	The spatial heterogeneity of the TME in ESCC remains unknown across different subregions	[35, 54, 55]
Lung adenocarcinoma (LUAD)	A. Expression levels are significantly lower than in normal lung tissue. B. Advanced-stage LUAD has lower expression than early-stage LUAD.	Increased expression of KLRB1 is positively correlated with overall survival in patients with LUAD	A. The prominent feature of the TME is immunosuppression, particularly the suppression of CD8 + T cells B. The expression of KLRB1 is typically accompanied by more abundant immune infiltration, particularly CD8 + T cells and NK cells. C. Compared to the early stages, the proportion of KLRB1-positive CD8-positive T cells significantly decreases in advanced LUAD	[2], 36– [38, 50]
Clear cell renal cell carcinoma (ccRCC)	The overall expression level of KLRB1 in tumor tissue is often higher than in some normal tissues	Higher KLRB1 expression is associated with lower survival rates	A. A large number of tumor-infiltrating T lymphocytes B. The tumor immune microenvironment (TIME) exhibits a unique paradoxical state: although tumors are highly infiltrated with immune cells, they are prone to immune escape C. Tumor cells produce cytokines such as IL-10 and TGF-β, which inhibit immune cell activation and promote the differentiation of Tregs. Tregs suppress the activity of effector T cells and promote tumor growth	[11, 32, 40, 41]
Testicular germ cell tumors (TGCT)	Compared to normal testicular tissue, the expression of KLRB1 in TGCT is significantly enhanced	It is not clear yet	The infiltration of CD4 + T cells is higher than that of CD8 + T cells	[29, 42]
Low-grade glioma	Compared to normal brain tissue, LGG tissue may exhibit higher or similar KLRB1 expression	High expression of KLRB1 indicates a poorer prognosis	A. Tregs infiltration was found to be positively correlated with glioma grade B. The infiltration of CD8 + T cells in tumors is negatively correlated with glioma grade	[2, 11, 44, 53]

Association between KLRB1 expression and prognosis in cancer patients

In most tumors, high expression of KLRB1 typically predicts a better prognosis; however, a few tumors show the opposite trend. In patients with HCC, the overall expression level of KLRB1 on peripheral or tumor-infiltrating NK cells and T cells is lower compared to healthy individuals. Further survival analysis confirmed that this lower expression level of CD161 is significantly associated with poorer clinical outcomes in HCC patients [34, 45, 46]. In CRC, high KLRB1 expression is identified as a favorable prognostic factor, correlating with improved overall survival and progression-free survival [47]. In BC, patients with low KLRB1 levels are characterized by older age, advanced disease stage, human epidermal growth factor receptor 2 positivity, and a significantly reduced probability of survival [48]. TNBC patients with low KLRB1 expression tend to have a poor prognosis, which may be attributed to insufficient infiltration of immune cells. Kaplan-Meier curve analysis shows that patients with high KLRB1 expression have a significantly longer progression-free survival and a lower risk of recurrence [49]. Similarly, in LUAD, reduced expression of KLRB1 is associated with a more aggressive tumor phenotype, specifically manifested as increased tumor volume, higher incidence of distant metastasis, and advanced pathological stage [50]. Conversely, increased KLRB1 expression is positively correlated with better overall survival and disease-specific survival in LUAD patients, further supporting its prognostic value [2]. In various cancers, high KLRB1 expression typically predicts a better prognosis, and the underlying mechanism may involve KLRB1 regulating key pathways, including cell signaling, which are central to tumor progression. KLRB1 is involved in interactions between T cell subsets and immune regulatory pathways, including the CD69-KLRB1 signaling axis, which is associated with the regulation of immunotherapy resistance [51]. Meanwhile, bioinformatics analysis reveals the association of KLRB1 with the immune microenvironment, finding that its expression is linked to the differentiation processes of immune cells and key immune checkpoint pathways such as PD-1/PD-L1. Overexpression experiments further confirm that KLRB1 can effectively inhibit the proliferation and migration abilities of tumor cells, suggesting its role as a tumor suppressor factor [50, 52]. However, there are also a few tumors where high KLRB1 expression is associated with a poorer prognosis. In clear cell renal cell carcinoma and low-grade gliomas, higher KLRB1 expression is linked to lower survival rates [11, 53]. In ESCC, knockdown of KLRB1 inhibits the growth of human ESCC cells, implying that low KLRB1 expression represents a better prognosis [54, 55]. The underlying reasons are not fully understood, and we speculate that this may stem from tumor heterogeneity and the possibility that KLRB1 is highly expressed on the surface of exhausted CD8 + T cells in these three types of tumors (Table 2).

Construction of a prognostic model combining KLRB1 with other clinical indicators

Integrating KLRB1 expression with established clinical parameters such as tumor stage and immune score has demonstrated enhanced prognostic accuracy across various cancers, underscoring the value of multifactorial risk models in oncology. In HCC, multiple studies have incorporated KLRB1 into multigene signatures, achieving effective patient risk stratification when combined with clinical characteristics. For instance, a risk model related to zinc homeostasis, which includes KLRB1 and four other genes, generated a nomogram by integrating clinical features that accurately predicted patient outcomes, with higher risk scores associated with poorer prognosis and immunosuppressive phenotypes [56]. Similarly, a gene signature linked to WNT score, combined with KLRB1, exhibited robust prognostic power; patients classified as high-risk displayed more advanced clinical characteristics and lower survival rates, validating the clinical utility of the model [57]. In ovarian cancer, a risk model integrating KLRB1 with immune and stromal scores effectively stratified patients based on survival, with high-risk individuals showing distinct immune infiltration patterns and drug sensitivities, highlighting the synergistic prognostic value of combining molecular and microenvironmental indicators [58, 59]. BC research has also constructed immune-related gene signatures including KLRB1, and when combined with clinical variables such as age and tumor stage, the resulting nomogram demonstrated higher predictive accuracy compared to traditional staging. These models correlate KLRB1 expression with immune cell infiltration and checkpoint expression, thereby revealing intrinsic connections between molecular features and tumor immune microenvironment characteristics associated with prognosis [60–62]. In bladder cancer, a study developed a seven-gene signature containing KLRB1 and integrated it with clinical factors such as lymphovascular invasion and metastasis status; the resulting prognostic nomogram achieved a concordance index of 0.73, demonstrating its clinical applicability in survival prediction [63]. Furthermore, in CRC, single-cell transcriptomic analysis revealed that KLRB1 expression in T cell subsets is an independent prognostic factor, and models incorporating clinical staging enhanced survival prediction and immunotherapy response assessment [51]. Collectively, these findings emphasize the significant contribution of KLRB1 to constructing multidimensional prognostic models when integrated with clinical staging and immune scores. These models not only improve the accuracy of risk stratification but also reflect underlying tumor-immune interactions, thereby guiding personalized treatment decisions. The consistent validation of KLRB1 incorporation in models across different tumor types and independent cohorts further supports its potential for clinical translation. Future efforts should focus on prospective validation and integrating KLRB1-based signatures into clinical workflows to optimize prognostic evaluation and therapeutic stratification.

The role of KLRB1 in tumor immunity

KLRB1-mediated mechanisms of tumor immune escape

The interaction between KLRB1 and its ligand CLEC2D has emerged as a critical axis influencing the progression and immune evasion of various cancers. Comprehensive pan-cancer analyses indicate that the CLEC2D expression ratio is elevated in most tumors compared to normal tissues and increases with advancing pathological stages, suggesting its dynamic role in tumor evolution. Notably, lower KLRB1 expression is associated with higher mortality rates, underscoring its complex involvement in tumor immunity. This expression pattern is influenced by factors such as lymphocyte infiltration, copy number variations, and DNA methylation, indicating that the regulation of KLRB1 is closely linked to the tumor immune landscape [64]. In HCC, KLRB1 expression on CD8 + T cells is associated with an innate-like, low-cytotoxicity phenotype. Unlike classical exhausted T cells, these KLRB1 + CD8+ T cells exhibit reduced clonal expansion and diminished effector functions, thereby promoting tumor immune evasion. This suggests that KLRB1 expression marks a dysfunctional T cell subset exploited by tumors to escape immune surveillance. KLRB1 is also involved in regulating macrophage polarization within the TME. Experimental knockdown of KLRB1 in tumor cells enhances tumor cell activity and promotes macrophage polarization from the M0 to the immunosuppressive M2 phenotype. This finding highlights the role of KLRB1 in shaping the immune environment by influencing macrophage behavior, thereby indirectly contributing to tumor immune evasion [65]. Furthermore, immune evasion in recurrent HCC involves impaired antigen presentation by dendritic cells, revealing multiple mechanisms by which KLRB1 promotes immunosuppression [66]. Similarly, in CRC, KLRB1 binds to the CLEC2D ligand to mediate immunosuppression via Tregs. Single-cell RNA sequencing reveals that TGFβ1 + Tregs expand in advanced CRC and interact with CD8 + T cells through KLRB1-CLEC2D signaling, involving other inhibitory pathways. This interaction promotes the exhaustion and apoptosis of CD8 + T cells, severely impairing anti-tumor immunity and facilitating tumor immune evasion. The role of Tregs in amplifying these immunosuppressive signals within the TME underscores KLRB1’s function as a mediator of immune checkpoint regulation, contributing to the establishment of a deeply immunosuppressive environment that drives CRC progression [67]. Overall, these studies elucidate the multi-layered mechanisms by which KLRB1 promotes immune evasion through its interaction with CLEC2D and its specific involvement in T cell exhaustion, macrophage polarization, and Treg-mediated immunosuppression. Small-molecule inhibitors targeting the KLRB1-CLEC2D axis (e.g., Forsythiaside A and RGD peptides identified through structure-based virtual screening) offer highly promising therapeutic avenues to disrupt these immunosuppressive interactions and restore anti-tumor immunity across various cancers [64].

KLRB1 regulates downstream signaling pathways

Ligand binding and signal initiation: The cytoplasmic tail of KLRB1 is a short peptide consisting of 45 amino acids. Unlike many classic inhibitory immune receptors, this cytoplasmic tail lacks typical strong consensus immunoreceptor tyrosine-based inhibitory motifs (ITIMs). However, sequence analysis reveals that this region contains a tyrosine residue located within an atypical motif. This tyrosine residue may function as a weak ITIM [13]. The tyrosine residue in this motif subsequently undergoes phosphorylation modification, thereby initiating the transmission of downstream inhibitory signals. The phosphorylated ITIM motif can specifically recruit intracellular tyrosine phosphatases, primarily SHP-1 and Src homology region 2 domain-containing phosphatase-2 (SHP-2) [10]. Core signal molecule dephosphorylation and pathway blockade: SHP regulates downstream signaling pathways through three mechanisms. Studies have shown that SHP-1 can directly bind to the NF-κB complex, inhibiting its phosphorylation and nuclear translocation, thereby suppressing the expression of downstream pro-inflammatory genes and reducing the production of cytokines (such as interleukin-1β and interleukin-6 ) [68]. The pathways regulating the functions of SHP-1 and SHP-2 involve stress activation within the MAPK family. The MAPK family members include three main subgroups: extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinases (JNKs), and p38 MAPK [69]. Research indicates that after activation of the JNK in the MAPK family, it induces gene transcription by phosphorylating pro-inflammatory transcription factors such as activator protein-1 (AP-1), driving the expression of cytokines such as IFN-γ and TNF-α. SHP-1 indirectly inhibits the nuclear translocation and activity of these transcription factors by blocking MAPK activation [69, 70]. In addition to its role in the NF-κB and MAPK pathways, SHP (primarily SHP-1) is also involved in the regulation of the PI3K/Akt pathway. SHP-1 specifically dephosphorylates tyrosine sites on the PI3K regulatory subunit p85, altering its phosphorylation state, which in turn affects its inhibitory effect on the p110 catalytic subunit. When p85 is in a non-phosphorylated state, its inhibitory effect on p110 is enhanced, leading to a significant reduction in the lipid kinase activity of PI3K, thereby blocking the phosphorylation and activation of Akt [71–73]. Given that the PI3K/Akt pathway is a core signal transduction pathway regulating immune cell activation, proliferation, and survival, SHP-1 effectively inhibits the activation of the entire pathway by dephosphorylating key molecules upstream (p85) and downstream (Akt) of the pathway. This inhibitory effect ultimately hinders the proliferation process of immune cells, reduces their survival capacity, and weakens their related effector functions, thereby playing an important role in the negative regulation of immune responses (Fig. 1).

Fig. 1.

KLRB1 Downstream Signaling Model. AKt: AKT serine/threonine kinase; AP-1:Activator Protein-1; SHP-1: Src homology 2 domain-containing phosphatase-1; SHP-2: Src homology 2 domain-containing phosphatase-1; JNK: c-Jun N-terminal kinase; PI3K: phosphoinositide 3-kinase; ITIM: Immunoreceptor Tyrosine-based Inhibitory Motif; NF-κB: Nuclear Factor kappa-light-chain-enhancer of activated B cells

The multifaceted role of KLRB1 in the tumor immune microenvironment

CD161, as a multifunctional receptor, plays a complex regulatory role in immune cells. Its expression on specific T cell subsets, such as CD161 + T memory cells, endows these cells with unique biological properties. The function of CD161 is dualistic: on one hand, it can act as an inhibitory receptor, suppressing the cytotoxicity of natural killer cells when bound to its ligand LLT1 [8, 9]; on the other hand, under specific conditions, it can also exert an activating effect. Research has found that the single CD161-LLT1 interaction is insufficient to activate T cells to produce IFN-γ. However, when this interaction synergizes with T cell receptor signaling (especially signals mediated via CD3), it can effectively promote T cell secretion of IFN-γ [7]. Furthermore, triggering CD161 signaling can significantly enhance the proliferative capacity of specific T cell subsets, including NKT cells and Th17 cells [24]. The underlying mechanism for this proliferation-promoting effect may lie in the CD161 co-stimulation-induced activation and nuclear translocation of key transcription factors such as nuclear factor of activated T cells (NFAT), NF-κB, and AP-1. These transcription factors work synergistically to initiate the transcription of various related genes that support T cell proliferation and survival. The regulatory role of CD161 is highly cell-type and function-specific. For example, the binding of LLT1 to CD161 does not affect the degranulation process of CD8 + T cells but partially inhibits the secretion of TNF-α by these cells [15]. T cell subsets expressing CD161, particularly CD161 + T memory cells, also exhibit significant tissue homing capabilities. These cells can home to vital organs such as the lungs, liver, intestines, pancreas, and brain, where they perform crucial immune surveillance functions. In these tissues, they can mount rapid responses to viral infections and exert significant anti-tumor effects [15]. In summary, the function of CD161 is highly dependent on its interacting ligands, co-stimulatory signals, and the cellular microenvironment, playing a key role in the dynamic balance between immune activation and inhibition. Its expression not only influences cell proliferation and effector functions by regulating downstream transcription factor networks but also determines the tissue distribution of specific T cell subsets and their capabilities in local immune responses (Fig. 2).

Fig. 2.

KLRB1 plays multifaceted roles in the tumor immune microenvironment

Potential of KLRB1 in tumor immunotherapy

The impact of KLRB1 on the response to immunotherapy and its underlying mechanisms

The expression of KLRB1 has become a significant factor influencing the response to immune checkpoint inhibitors (ICIs). Patients exhibiting high KLRB1 expression are more likely to achieve favorable clinical outcomes following ICI treatment. For instance, in HCC, high KLRB1 expression is associated with increased infiltration of CD8 + T cells and other immune effector cells. Elevated KLRB1 levels are closely linked to improved ICI efficacy, indicating its potential as a biomarker for predicting ICI responsiveness [65, 74]. Beyond this, anti-CD161 therapy shows promising prospects in tumor immunotherapy. Recent studies have demonstrated that blocking CD161 can enhance the cytotoxic activity of T cells against tumor cells, thereby improving the effectiveness of immunotherapeutic approaches. Research on glioma-infiltrating T cells has shown that CD161 inactivation or antibody-mediated blockade can boost T cell killing capacity against glioma cells and strengthen anti-tumor immune responses in vivo, highlighting the role of CD161 as a novel inhibitory receptor and immunotherapeutic target [43]. In MSI-H colorectal cancer, exhausted CD8 + T cells expressing high levels of KLRB1 are significantly correlated with pathological complete response to neoadjuvant immune checkpoint inhibitors, suggesting their potential as predictive biomarkers and therapeutic targets [75]. Similarly, single-cell transcriptomic analysis has revealed that the KLRB1-CLEC2D interaction plays a crucial role in immune evasion by regulating T cell exhaustion and apoptosis. This mechanism has been particularly observed in CRC liver metastases, further supporting the therapeutic potential of blocking this signaling axis [76]. In head and neck squamous cell carcinoma, high expression of the KLRB1-CLEC2D axis has been identified as a major immune checkpoint, surpassing the classical PD-1/PD-L1 pathway, and is associated with poorer immunotherapy responses, underscoring its potential as a novel immune checkpoint target [77]. In HPV-driven oropharyngeal cancer, CD161 expression marks a subset of cytotoxic CD8 + T lymphocytes with an inflammatory phenotype. Despite expressing exhaustion markers, these cells retain functional reversibility and can be reactivated through immune checkpoint blockade [78]. These findings suggest that inhibitors targeting KLRB1 are expected to effectively reconstruct anti-tumor immune responses by blocking immunosuppressive signals [64, 67]. Further research in HPV16 + tumors has shown that CD4 + CD161+ effector memory T cells express the transcription activator SOX4, which enhances TCR signaling and enables rapid responses to suboptimal antigen stimulation. The dynamic regulation of CD161 expression is co-modulated by endogenous and exogenous factors, indicating that targeting CD161 may modulate T cell activation thresholds and optimize anti-tumor immune efficacy [21]. In summary, these findings highlight the multifaceted role of KLRB1/CD161 in regulating anti-tumor immunity. Blocking CD161 can enhance the cytotoxicity of exhausted T cells and remodel the tumor immune microenvironment, offering a novel checkpoint pathway distinct from the classical PD-1/PD-L1 and CTLA-4 axes. The current development of small-molecule inhibitors and antibodies targeting the KLRB1-CLEC2D interaction holds promise for advancing personalized immunotherapy strategies and improving the prognosis of patients with various malignancies.

Relationship between KLRB1 and chemotherapeutic drug sensitivity

In HCC, patients with low KLRB1 expression exhibit an immune-cold TME and a poorer response to transcatheter arterial chemoembolization, while higher KLRB1 levels are associated with better chemotherapy effect, suggesting that KLRB1 expression may modulate the tumor immune microenvironment to enhance chemotherapy effect [79]. Similarly, in BC, KLRB1 is part of a CD8 + T-cell gene signature that constitutes a feature enhancing chemotherapy response. Compared to adjacent normal tissues, KLRB1 expression levels are significantly reduced in tumor tissues, and patients with higher KLRB1 expression show better chemotherapy responses, indicating that KLRB1 may promote immune-mediated tumor suppression in synergy with chemotherapy [80]. In CRC, single-cell transcriptomic studies reveal that downregulation of KLRB1 is associated with drug resistance to chemotherapy. The CD69-KLRB1 signaling axis is implicated in resistance mechanisms, where reduced KLRB1 expression correlates with poorer clinical outcomes and decreased treatment sensitivity, making KLRB1 a promising biomarker for predicting chemotherapy response [51]. Furthermore, studies on cancer-associated fibroblasts heterogeneity identify KLRB1 as one of the core genes related to drug sensitivity, suggesting that KLRB1 expression in the TME not only affects immune cells but also stromal components influencing chemotherapy effect [81]. In hematological malignancies such as acute myeloid leukemia (AML), interactions involving NK cells and macrophages with KLRB1 expression are found to regulate chemotherapy resistance, where specific ligand-receptor pairs like CLEC2B-KLRB1 mediate intercellular communication among immune cells, thereby affecting chemotherapy tolerance [82]. These findings highlight the critical role of KLRB1 in modulating chemotherapy resistance by mediating immune cell communication. The above evidence further reinforces the concept that KLRB1 expression reflects a more active immune environment conducive to effective chemotherapy. Overall, these studies demonstrate that KLRB1 expression influences chemotherapy drug sensitivity in various cancers by regulating immune cell infiltration, immune checkpoint activity, and tumor-stroma interactions. This multifaceted role makes KLRB1 a valuable biomarker for predicting chemotherapy response and a potential target for enhancing chemotherapy sensitivity through immune modulation, thereby advancing the development of personalized cancer treatment paradigms.

The role of KLRB1 in non-tumor immune-related diseases

The role of KLRB1 in the immunopathology and prognosis of sepsis

Sepsis is a complex systemic inflammatory syndrome characterized by dysregulated immune responses, leading to organ dysfunction and high mortality, especially in intensive care units. The immunological relevance of KLRB1 in sepsis lies in its role in regulating the functions of NK cells and T cells, which are crucial for pathogen clearance and immune homeostasis. Functional enrichment analysis reveals that KLRB1 is enriched in pathways regulating leukocyte activation, immune effector processes, and neutrophil degranulation [83, 84]. Further studies based on protein-protein interaction networks and machine learning algorithms have identified KLRB1 as a key immune gene associated with sepsis progression and immune dysregulation [83, 85]. Moreover, the intersection of sepsis with related inflammatory conditions, such as sepsis-induced acute respiratory distress syndrome, reveals KLRB1 as a shared core gene, indicating its broader involvement in systemic inflammatory responses and its potential as a therapeutic target [86]. These findings are crucial for understanding the immunopathogenesis of sepsis. Recent bioinformatic analyses consistently show that KLRB1 expression is significantly lower in sepsis patients compared to healthy controls. Multiple transcriptomic datasets, including GSE54514, GSE57065, GSE69528, GSE95233, and GSE131761, have identified KLRB1 as a core gene with reduced expression in sepsis patients, a finding further validated by quantitative real-time Polymerase Chain Reaction (PCR) [87]. Notably, the downregulation of KLRB1 is associated with poor clinical prognosis. Comparative analysis shows that sepsis patients with poor prognosis exhibit significantly lower KLRB1 expression compared to those with good prognosis, suggesting that KLRB1 expression levels have potential as a prognostic biomarker [87]. Considering these findings, KLRB1 is not only a biomarker reflecting the immune status and disease severity in sepsis but also a potential therapeutic target for modulating immune responses to improve patient prognosis.

The role of KLRB1 in autoimmune diseases

KLRB1 has emerged as a crucial immunomodulatory molecule involved in various autoimmune diseases, including psoriasis [88], RA [89, 90], systemic lupus erythematosus (SLE) [91], and inflammatory bowel disease (IBD) [92]. In these conditions, abnormal expression of KLRB1 is commonly observed, driving dysregulated activation of immune cells and perpetuation of inflammatory responses. In psoriasis, dysregulated expression of KLRB1 on the surface of NK cells and T-cell subsets may affect cytotoxicity and cytokine production, thereby exacerbating tissue damage and chronic inflammation. In RA, KLRB1 expression is elevated in immune cell subsets associated with disease pathogenesis. Single-cell immunophenotyping studies have found that CCR2 + CD4+ T cells expand in individuals at high risk for RA, and these cells highly express KLRB1 along with other Th17- and Th22-related markers, suggesting a role for KLRB1 in early disease development and immune activation prior to clinical onset [93]. Furthermore, KLRB1 is associated with the characteristic immune heterogeneity of RA, with its expression correlating with alterations in the bone marrow immune profile and potentially serving as a biomarker linking RA to hematological malignancies such as AML [94]. Similarly, in SLE and IBD, KLRB1 is one of a set of common diagnostic markers reflecting shared pathogenic pathways involving programmed cell death and inflammatory signaling, highlighting its involvement in immune cell infiltration and tissue inflammation [92]. Overall, KLRB1 plays multifaceted regulatory roles in autoimmune diseases, where its aberrant expression not only impacts innate and adaptive immune components but also directly participates in immune cell activation and inflammatory cascades.

Regulatory role of KLRB1 in various aging-related pathological processes

Aging is a major risk factor for osteoporosis (OP), a disease characterized by reduced bone mass and increased fracture risk, partly due to alterations in immune system function, a phenomenon known as immunosenescence [95]. Alterations in KLRB1 expression may reflect changes in immune cell function, leading to chronic low-grade inflammation (“inflammaging”) and disrupting bone homeostasis. Notably, CD4 + effector memory T cells (CD4 + TEM) are increased in both aging and OP samples, highlighting the central role of this subset in the pathogenesis of osteoporosis. Within these cells, KLRB1 expression is significantly upregulated [96]. Mendelian randomization analysis further supports a causal association between KLRB1 expression and susceptibility to osteoporosis, suggesting that KLRB1 may drive disease progression by modulating T cell interactions within the bone microenvironment [96]. The upregulation of KLRB1 in CD4 + TEM cells may enhance their communication with other immune and stromal cells, potentially influencing inflammatory pathways and osteoclastogenesis, which are critical for bone remodeling and loss during aging. This aligns with the concept of immunosenescence, which involves not only quantitative changes in immune cells but also characteristic alterations in receptor expression profiles, thereby affecting immune regulation and tissue homeostasis. Additionally, the role of KLRB1 in immune regulation has been emphasized in other aging-related contexts. For example, in studies comparing the immune microenvironment of CRC across different age groups, KLRB1 expression was higher in patients of typical onset age than in early-onset patients, indicating its role in age-dependent immune regulation [97]. Although this study focused on cancer, the increased expression of KLRB1 in the elderly supports its broader role in aging immunity. Furthermore, interactions between KLRB1 and other immune regulatory molecules have been implicated in cardiovascular complications of aging, such as myocardial infarction associated with hypertension, where KLRB1 was identified as one of the differentially expressed genes linked to disease progression [98, 99]. In summary, these findings underscore the critical role of KLRB1 in various aging processes.

Future research directions and clinical application prospects of KLRB1

In-depth analysis of the KLRB1 molecular mechanism

Understanding the signaling pathways and regulatory networks of KLRB1 in immune cells is crucial for elucidating its role in tumor immunity and disease prognosis. Recent studies emphasize that KLRB1 expression affects immune cell activation, cytokine secretion, and immune checkpoint regulation, but the specific molecular mechanisms still require clarification. In T cells, KLRB1 expression marks an activated phenotype, enhancing proliferation and cytokine production. For example, in primary Sjögren’s syndrome, CD4 + KLRB1+ T cells show increased activation markers and secrete pro-inflammatory cytokines, indicating their involvement in T cell function [100]. In glioma, KLRB1 is enriched in tumor-infiltrating T cells, acting as an inhibitory receptor to promote immune escape; blocking KLRB1 can enhance anti-tumor killing effects [43]. At the signal transduction level, KLRB1 regulates immune activation and exhaustion pathways by binding to ligands. In adenocarcinoma of the lung, its expression is associated with pathways such as NF-κB and PD-1/PD-L1, suggesting potential interactions with other checkpoints to modulate the TME. Additionally, KLRB1 expression correlates with the infiltration and functional status of various immune cells, highlighting its role in reshaping the immune microenvironment in cancer [32, 34]. The interaction between KLRB1 and its ligand CLEC2D is a key immune checkpoint axis, with its ratio increasing with tumor progression, promoting immune escape; small molecule inhibitors can disrupt this interaction, offering new therapeutic avenues [64]. This axis regulates interactions between immune cells, potentially affecting T cell exhaustion and regulatory T cell function. KLRB1 expression is also influenced by epigenetic and post-transcriptional regulation, such as m6A methylation enhancing its expression and alleviating tissue damage, revealing a regulatory axis that may be associated with immune diseases and tumors [101]. KLRB1 expression is dynamically regulated in diseases, such as being associated with recurrence and immune activation in psoriasis, marking functional T cell subsets [102]; in systemic sclerosis, KLRB1 + CD8+ T cells promote tissue damage and fibrosis, demonstrating its context-dependent role [103]. In summary, KLRB1, as a regulatory receptor, influences immune cell activation, exhaustion, and interactions with other checkpoints, with its expression and function closely related to the TME and disease prognosis. Future research should focus on dissecting its downstream signaling cascades, mapping interactions with other molecules, and understanding how its regulation affects immune plasticity and anti-tumor immunity, which is essential for leveraging KLRB1 as a therapeutic target and biomarker.

Development of KLRB1 as a multi-disease biomarker

KLRB1 encodes the CD161 receptor, which is primarily expressed on NK cells and certain T cells, influencing cytotoxicity and immune microenvironment regulation, thereby providing a foundation for biomarker development. Pan-cancer analyses have elucidated the role of KLRB1 in immune infiltration, microenvironment remodeling, and the prediction of therapeutic responses [11, 62]. For example, in BC, its downregulation is associated with poorer survival and positively correlates with immune cell infiltration. Machine learning models incorporating KLRB1 expression can predict patient survival and immune status. In HCC, reduced KLRB1 expression on peripheral immune cells is linked to poor prognosis [34, 65]. Additionally, gene signatures including KLRB1 are also associated with prognosis. In LUAD, its reduction correlates with advanced disease stages and worse survival. In gastric cancer tissues, KLRB1 expression typically shows a downregulated trend. To advance the translation of KLRB1 from basic research to clinical applications in malignancies such as gastric cancer, there is an urgent need to establish a systematic biomarker prioritization strategy [104]. This strategy should be based on the integration of multidimensional evidence to ensure the full evaluation of the clinical translation potential of candidate markers. Beyond cancer, KLRB1 also serves as a biomarker for infectious and inflammatory diseases. In COVID-19, low expression of KLRB1 in the nasopharyngeal mucosa can predict severe progression and mortality risk [105]. In sepsis, KLRB1 is one of the key downregulated genes [83, 84, 106]. In autoimmune diseases such as primary Sjögren’s syndrome and systemic juvenile idiopathic arthritis, increased KLRB1 expression in activated T cells is associated with disease activity [100, 107]. Furthermore, KLRB1 has been identified as a shared diagnostic marker for major depressive disorder and SLE [108]. In psoriasis, its upregulation indicates its potential as a biomarker [88]. The integration of multi-omics data further enhances the application efficacy of KLRB1-based biomarkers. The development of tools based on KLRB1 benefits from its consistent associations with immune cells and pathways across different diseases. Single-cell analyses have identified KLRB1 expression in T cell and NK cell subsets, highlighting its role in immune cell heterogeneity and function [109]. Additionally, epigenetic regulation of KLRB1 expression provides insights into biomarker stability [101]. In practice, KLRB1 expression can be quantified using various platforms, facilitating its incorporation into clinical workflows [89, 105]. Integrating KLRB1 expression data with other omics layers enables the construction of optimized disease risk assessment models [59, 76]. Such integrative strategies are crucial for advancing precision medicine.

Application potential of KLRB1 in combination immunotherapy

KLRB1 regulates immune responses in the TME, and its potential as a target for combination immunotherapy is increasingly recognized. As a recent study points out, overcoming therapeutic bottlenecks in HCC requires exploring new targets such as KLRB1. Investigating KLRB1 may bring new breakthroughs in immunotherapy for liver cancer [110]. In HCC, elevated KLRB1 expression is associated with increased infiltration of CD8 + T cells and dendritic cells, improved survival, and better responses to immune checkpoint blockade (ICB) therapy [65, 74]. KLRB1 also regulates macrophage polarization in the TME. Inhibition of KLRB1 expression can promote M2 macrophage polarization, which is linked to tumor progression and immune evasion. Targeting KLRB1 may enhance T cell and NK cell cytotoxicity and reprogram macrophage-mediated immunosuppression, thereby improving the efficacy of immunotherapy. In BC, KLRB1 has been identified as a key prognostic gene associated with increased NK cell infiltration and enhanced cytotoxicity, which is crucial for effective immunotherapy [62]. Additionally, in hormone receptor-positive breast cancer, KLRB1 is part of a lipid metabolism and ferroptosis-related gene signature used to stratify patients’ responsiveness to immunotherapy, supporting its role in predicting and optimizing immunotherapy outcomes [111]. In glioma, CD161 is an inhibitory receptor on tumor-infiltrating T cells. Blocking or inactivating CD161 enhances T cell-mediated tumor killing, suggesting that targeting KLRB1 may synergize with ICIs [43]. In CRC, downregulation of the CD69-KLRB1 signaling pathway leads to resistance to anti-PD-1 therapy, highlighting the importance of the KLRB1 pathway in modulating responses to immune checkpoints, and combination targeting may reverse this resistance [51]. KLRB1 expression is not only closely associated with tertiary lymphoid structures and cancer-associated fibroblast signatures, but this association is consistent with improved responses to immunotherapy, suggesting it may regulate a broader immune network within tumors [81, 112]. Combining KLRB1 with existing ICIs may overcome immune tolerance and enhance anti-tumor immunity. In summary, KLRB1 holds promising prospects as a target for combination immunotherapy. Furthermore, to examine the causal relationship between KLRB1 and cancer risk or treatment response, emerging genetic methods such as Mendelian randomization could be employed in the future [113]. More clinical trials targeting KLRB1 are needed to evaluate the efficacy of combination therapies, thereby fully unlocking its potential in cancer immunotherapy.

Conclusion

The relationship between KLRB1 and the tumor immune microenvironment constitutes the core theme of this review. KLRB1 regulates immune cell activation and participates in tumor escape, reflecting the complexity of immune regulation. As a prognostic marker and therapeutic target, the expression of KLRB1 is associated with clinical outcomes, which can guide patient stratification and personalized therapy, potentially enhancing the efficacy of existing treatments or providing new approaches. However, the heterogeneity of the tumor microenvironment necessitates a cautious strategy. Future research should focus on the signal transduction mechanisms of KLRB1 and therapeutic strategies, including investigating whether its intracellular signals are mediated by adapter proteins (such as the SAP family) to regulate the mTOR/STAT pathway, utilizing techniques like Co-IP and phosphoprotein profiling to monitor dynamic changes in the phosphorylation status of STAT, mTOR, and ERK following agonist stimulation or blocker treatment of the receptor. In terms of therapeutic intervention, the short-term blocking effect on enhancing the ability of effector cells to clear pathogens or kill tumors should be evaluated, as well as the risk of long-term blocking inducing immunopathology or autoimmune response, by observing the effects of antibody or genetic interventions in mouse models. In summary, KLRB1 is a key molecule in immunology and oncology, and in-depth analysis of its network is crucial for clinical translation, potentially overcoming current therapeutic limitations and advancing the development of precision immunotherapy.

Author contributions

Conceptualization: JiaMei Hu, Jiayu Guan, Shaoying Li, Original draft: JiaMei Hu, Jiayu Guan, Review and editing: Liling Zhang, Shaoying Li.

Funding

Guangdong Provincial Science and Technology Plan Project (No.2015A020211003).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.