SIGLEC15: An Emerging Immune Checkpoint Target in Tumor Immunotherapy

SIGLEC15 is an emerging immune checkpoint molecule widely expressed in various tumors, closely associated with immune evasion, treatment resistance, and poor prognosis. It plays a key role in tumor immunosuppression by inhibiting T cell activity, inducing a non-inflammatory tumor microenvironment, and regulating the polarization of tumor-associated macrophages. In recent years, strategies targeting SIGLEC15, including monoclonal antibodies, bispecific antibodies, CAR-T cells, and gene silencing, have developed rapidly, providing new avenues to overcome the limitations of PD-1/PD-L1 therapy. This article reviews the structure and function of SIGLEC15, systematically analyzes its signaling pathways, disease relevance, and progress in drug development, aiming to provide a theoretical basis for subsequent immunotherapy research and new drug development.

1. The Emergence and Significance of SIGLEC15 Research

2. Biological Characteristics and Expression Pattern of SIGLEC15

3. Mechanism of Action of SIGLEC15 in the Tumor Microenvironment

4. Signal Transduction Pathways of SIGLEC15

5. SIGLEC15 and Related Diseases

6. Progress in Drug Development Targeting SIGLEC15

7. SIGLEC15 Research Tools

1. The Emergence and Significance of SIGLEC15 Research

The advent of immune checkpoint inhibitors has revolutionized cancer treatment, but a significant number of patients do not respond to PD-1/PD-L1 therapy or develop acquired resistance. Finding new immune regulatory targets has become crucial for advancing immunotherapy. Sialic acid-binding Ig-like lectin 15 (SIGLEC15), a member of the Siglec family, is emerging as a research hotspot for the next generation of immune checkpoints due to its unique immunosuppressive functions and high expression in various tumors ^[1,2].

Studies have shown that SIGLEC15 is highly expressed in multiple tumor types and is closely associated with poor prognosis. Unlike PD-L1, the upregulation of SIGLEC15 often occurs in PD-L1-negative or immunologically "cold" tumors ^[1-3], suggesting it may mediate tumor immune escape through independent pathways. Therefore, in-depth analysis of SIGLEC15's mechanism of action and targeting strategies is of great significance for improving responses to tumor immunotherapy.

2. Biological Characteristics and Expression Pattern of SIGLEC15

SIGLEC15 is an important member of the Siglec family, consisting of an extracellular immunoglobulin-like domain, a transmembrane region, and a short intracellular tail. Its extracellular structure recognizes sialylated glycans and is involved in intercellular signaling regulation ^[4]. Although the intracellular region lacks typical immunoreceptor tyrosine-based inhibitory motifs (ITIMs), it can form complexes with adaptor proteins such as DAP12 via charged residues in its transmembrane segment, thereby mediating downstream signaling ^[5].

Research indicates that SIGLEC15 is significantly upregulated in various malignancies including hepatocellular carcinoma (HCC) ^[4], thyroid cancer ^[6], colon adenocarcinoma ^[1], glioma ^[8], bladder cancer ^[2], and B-cell acute lymphoblastic leukemia (B-ALL) ^[7]. Its high expression is often associated with reduced CD8+ T cell infiltration, increased immunosuppressive cells, and decreased overall survival. Immunofluorescence studies have found that SIGLEC15 co-localizes with the M2 macrophage marker CD163, suggesting its role in regulating macrophage polarization within the tumor immune microenvironment ^[8].

3. Mechanism of Action of SIGLEC15 in the Tumor Microenvironment

3.1 Suppression of T Cell Function

SIGLEC15 achieves immunosuppression by inhibiting CD8+ T cell activity, reducing cytotoxicity, and impairing T cell survival. Its high expression is often correlated with decreased levels of chemokines (such as CXCL9/10) and a lower T-cell inflammation score ^[10]. In B-ALL models, knockout of SIGLEC15 promotes CD8+ T cell expansion and enhances anti-tumor immune responses ^[7].

3.2 Synergy with Tumor-Associated Macrophages (TAMs)

SIGLEC15 is highly expressed on M2-type TAMs. It exacerbates local immune tolerance by enhancing the secretion of immunosuppressive factors like TGF-β and IL-10 ^[11,12]. Simultaneously, it promotes angiogenesis and stroma remodeling, creating a microenvironment conducive to tumor metastasis.

3.3 Relationship with the PD-L1 Pathway

The expression of SIGLEC15 and PD-L1 exhibits complementary or independent patterns across different tumor types ^[1,4]. High SIGLEC15 levels often accompany low PD-L1 expression and an immunologically cold microenvironment, rendering tumors insensitive to traditional immune checkpoint inhibitors ^[2]. Combined blockade of both significantly improves the response rate to immunotherapy.

4. Signal Transduction Pathways of SIGLEC15

4.1 ITAM/ITIM Signaling Modules and DAP12-Mediated Activation Mechanism

Signal balance in immune cells is co-regulated by activating ITAM (Immunoreceptor Tyrosine-based Activation Motif) and inhibitory ITIM (Immunoreceptor Tyrosine-based Inhibitory Motif) modules. Although SIGLEC15 lacks a typical ITIM structure, its transmembrane region contains positively charged residues that enable binding to the ITAM-containing adaptor protein DAP12 ^[13]. Upon phosphorylation by Src family kinases (such as Lyn or Fgr), DAP12 recruits Syk kinase, initiating downstream cascade signals including the PI3K/AKT and MAPK/ERK pathways, thereby regulating cell activation and differentiation ^[14]. This suggests that SIGLEC15 can function as an "activating" regulatory receptor in specific contexts, influencing immune cell responses via the DAP12-Syk axis.

4.2 Syk/Src Kinase Pathways and Immune Regulation

Syk family kinases hold a central position in immune signal transduction. The SIGLEC15-DAP12-Syk pathway can promote functional changes in myeloid cells, enhancing the immunosuppressive properties of monocytes/macrophages. Some studies indicate that Syk activation can upregulate STAT3 and NFκB signaling, driving the expression of immunosuppressive cytokines (e.g., IL-10, TGF-β) ^[15]. Furthermore, SIGLEC15 may regulate integrin adhesion molecule activity via Src kinases, affecting cell migration and immune synapse formation.

4.3 Bidirectional Regulation with NFκB and EGFR Pathways

Studies in leukemia and thyroid cancer have found that NFκB activation can induce transcriptional upregulation of SIGLEC15, forming a positive feedback loop ^[7,16]. Concurrently, SIGLEC15 can directly interact with EGFR, stabilizing its protein structure and enhancing downstream ERK and PI3K/AKT signaling ^[16]. This mechanism not only promotes tumor cell migration and invasion but also reveals non-immune roles for SIGLEC15 in tumor progression.

Overall, the SIGLEC15 signaling network spans immunosuppressive and tumor-promoting pathways, exerting multi-layered effects on the tumor microenvironment through coordinated regulation via the DAP12-Syk, NFκB, and EGFR axes.

5. SIGLEC15 and Related Diseases

5.1 Solid Tumors

SIGLEC15 is highly expressed in various solid tumors and is an independent indicator of poor prognosis.

In HCC, SIGLEC15 promotes immune evasion by inducing CD8+ T cell apoptosis, and its blockade can restore immune responses ^[4]. In bladder cancer, its high expression is associated with the formation of an immunologically cold microenvironment, insensitivity to immunotherapy, and an increased risk of hyperprogression ^[2,10]. In thyroid cancer, high SIGLEC15 expression is closely linked to immune exhaustion and enhanced invasiveness ^[6].

In glioma, SIGLEC15 levels increase with WHO grade and are closely associated with M2-type TAMs, suggesting its role in remodeling the brain tumor immune microenvironment ^[8]. Studies in fibrosarcoma show that knocking down SIGLEC15 significantly slows tumor growth and enhances sensitivity to radiotherapy and chemotherapy ^[9]. Furthermore, its high expression in lung adenocarcinoma spinal metastasis ^[5] and ovarian cancer ^[17] has also been confirmed to be closely related to aggressive metastasis and immune evasion.

5.2 Hematologic Malignancies

In B-ALL, NFκB signaling activation directly upregulates SIGLEC15 transcription ^[7], promoting the secretion of immunosuppressive cytokines and impairing T cell activity. Genetic knockout of SIGLEC15 enhances immune surveillance and improves the leukemia microenvironment. Soluble SIGLEC15 has been detected in patient plasma, suggesting its potential as a biomarker for diagnosis and treatment response prediction.

5.3 Bone Metabolism and Inflammatory Diseases

SIGLEC15 regulates osteoclast differentiation and bone resorption, making it an important factor in bone homeostasis. Research indicates that SIGLEC15 modulates RANKL signaling in the bone microenvironment, affecting osteoclast formation ^[18]. In breast cancer bone metastasis models, it promotes the formation of bone metastases by inhibiting CD8+ T cell activation ^[18]. Additionally, SIGLEC15 may be involved in the inflammatory regulation of rheumatoid arthritis, and its association with the DAP12-Syk pathway hints at its role in inflammatory immune regulation ^[13].

6. Progress in Drug Development Targeting SIGLEC15

As an emerging immunosuppressive target in the tumor microenvironment, independent of PD-L1 expression, SIGLEC15 offers a new direction to overcome PD-1/PD-L1 resistance. Current research and development are primarily focused on monoclonal antibodies. Among them, NC-318 and PYX-106 have entered Phase II and Phase I clinical trials for non-small cell lung cancer and solid tumors, respectively, while several other candidates are in the preclinical stage. Research in this field is exploring not only their potential as monotherapies but also actively developing combination regimens with existing immunotherapies and expanding into non-oncological areas such as bone diseases. Some investigational candidates are listed in the table below:

Drug	Mechanism of Action	Drug Type	Indication (Disease Name)	Research Institution	Highest Stage
NC-318	Siglec-15 Inhibitor	Monoclonal Antibody	Advanced Non-Small Cell Lung Cancer	NextCure, Inc.	Phase II
PYX-106	Siglec-15 Inhibitor \| ADCC	Monoclonal Antibody	Advanced Malignant Solid Tumors \| Solid Tumors \| Non-Small Cell Lung Cancer \| Thyroid Cancer	Pyxis Oncology, Inc. \| Biosion (Nanjing) Inc.	Phase I
S15-4E6A	Siglec-15 Inhibitor	Biologics	Lung Adenocarcinoma	Nanjing Medical University	Preclinical
NP-159	Siglec-15 Inhibitor	Monoclonal Antibody	Spinal Cord Injury	NextCure, Inc.	Preclinical
SHG-8	Siglec-15 Inhibitor	Small Molecule	Colorectal Cancer	University of Hertfordshire	Preclinical
PBI-108	PD-1 Inhibitor \| Siglec-15 Inhibitor	Bispecific Antibody	Solid Tumors	Protheragen, Inc.	Preclinical
BCG-008	Siglec-15 Inhibitor \| ADCC \| T cell stimulator	Monoclonal Antibody	Solid Tumors	Biocytogen (Beijing) Co., Ltd.	Preclinical

(Data as of October 31, 2025, sourced from Synapse)

7. SIGLEC15 Research Tools

SIGLEC15, as a novel immune checkpoint molecule, plays a central role in tumor immunosuppression. Its signaling pathways span both immune and pro-tumor dimensions, coordinately regulating cell fate through the DAP12-Syk, NFκB, and EGFR axes. Various therapeutic strategies targeting SIGLEC15 (monoclonal antibodies, bispecific antibodies, CAR-T, gene silencing, etc.) are rapidly developing, demonstrating potential to break through PD-1/PD-L1 resistance. CUSABIO provides SIGLEC15 recombinant proteins, antibodies, and ELISA kits to support your related mechanism research and SIGLEC15-targeted drug development.

● SIGLEC15 Recombinant Protein

Recombinant Human Sialic acid-binding Ig-like lectin 15 (SIGLEC15), partial (Active); CSB-MP761623HU

● SIGLEC15 Antibody

SIGLEC15 Recombinant Monoclonal Antibody; CSB-RA761623MA3HU

SIGLEC15 Recombinant Monoclonal Antibody; CSB-RA761623MA2HU

References

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[2] Jiao Hu, Anze Yu, Belaydi Othmane, D. Qiu, Huihuang Li, Chao Li, Peihua Liu, Wenbiao Ren, Minfeng Chen, G. Gong, Xi Guo, Huihui Zhang, Jinbo Chen, X. Zu.(2021). Siglec15 shapes a non-inflamed tumor microenvironment and predicts the molecular subtype in bladder cancer.

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