MSA-2, a powerful orally available non-nucleotide STING agonist, binds to STING as a noncovalent dimer with nanomolar affinity. It displays EC50 values of 8.3 and 24 μM for human STING isoforms WT and HAQ, respectively. MSA-2 promotes interferon-β secretion in tumors, leads to tumor regression with lasting antitumor immunity, and enhances the effectiveness of anti-PD-1 therapy in syngeneic mouse tumor models[1][2].
体内研究
MSA-2, administered either orally (PO) or subcutaneously (SC), achieves similar levels of exposure in both tumor and plasma. Additionally, MSA-2 demonstrates dose-dependent antitumor effects whether delivered intratumorally (IT), subcutaneously (SC), or orally (PO). Dosing regimens have been established that result in complete tumor regression in 80 to 100% of the animals treated[1].
MSA-2 (PO: 60 mg/kg or SC: 50 mg/kg; single dose) effectively inhibits tumor growth and significantly increases levels of IFN-β, interleukin-6 (IL-6), and TNF-α within the tumor[1].
MSA-2 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Bone marrow-derived macrophages (BMDM)
0.01 mg/ml
1 day
To assess the effect of MSA-2 on macrophage polarization, results showed MSA-2 significantly increased M1-like markers (CD86, H-2Kd) and proinflammatory cytokines (IFN-β, IL-6, TNF-α).
J Hematol Oncol. 2022 Oct 8;15(1):142.
Bone marrow-derived dendritic cells (BMDC)
0.01 mg/ml
1 day
To evaluate the effect of MSA-2 on STING pathway activation, results showed MSA-2 significantly upregulated DC maturation markers (CD80, CD86, H-2Kd, I-A/I-E) and proinflammatory cytokines (IFN-β, IL-6, TNF-α).
J Hematol Oncol. 2022 Oct 8;15(1):142.
THP-1 cells
20 µM
1 hour
Evaluate the activation effect of MSA-2 on the cGAS/STING signaling pathway in THP-1 cells
BMC Med. 2024 Mar 5;22(1):96.
D2.0R cells
10-50 µM
16-48 hours
To evaluate the effect of MSA-2 on NK cell killing of D2.0R cells, results showed MSA-2 significantly enhanced NK cell killing
Cancer Res. 2024 Oct 15;84(20):3337-3353.
Short-term expanded Vδ2 γδ T-cell lines
25 µM
24 hours
MSA-2 co-stimulated cytokine induction but induced cell death
Oncoimmunology. 2022 Feb 1;11(1):2030021.
Monocytes
25 µM
24 hours
MSA-2 stimulated IL-1β and TNF-α secretion and induced cell death
Oncoimmunology. 2022 Feb 1;11(1):2030021.
Vδ2 T cells
25 µM
24 hours
MSA-2 co-stimulated cytokine induction but inhibited proliferation
Oncoimmunology. 2022 Feb 1;11(1):2030021.
THP1 cells
40 µM
24 hours
To validate STING activation by SAProsome-3 in THP1 cells, results showed upregulation of IFN-β, TNF-α, and CXCL10 mRNA expression and activation of STING downstream signaling.
Nat Commun. 2023 Jul 31;14(1):4584.
Bone marrow-derived dendritic cells (BMDC)
40 µM
24 hours
To evaluate the STING pathway activation by SAProsomes, results showed significant upregulation of IFN-β, TNF-α, and CXCL10 mRNA expression and promotion of DC maturation.
Nat Commun. 2023 Jul 31;14(1):4584.
STING knockout PK-15 cells
30 µM
24 hours
To verify whether the antiviral effect of MSA-2 depends on STING, results showed MSA-2 failed to inhibit SVV replication in STING knockout cells.
Viruses. 2023 Oct 24;15(11):2138.
PK-15 cells
30 µM
24 hours
To evaluate the inhibitory effect of MSA-2 on SVV replication, results showed MSA-2 significantly reduced viral RNA levels and virus titers.
Viruses. 2023 Oct 24;15(11):2138.
RAW264.7 cells
10, 50 µM
24 hours
Evaluate the effect of MSA-2 and MSA-2-Pt on the secretion of IFN-β by RAW264.7 cells. The results showed that both could trigger the secretion of IFN-β.
ACS Omega. 2024 Jan 3;9(2):2650-2656.
MC38 cells
25, 50, 75, 100, 200, 300 µM
24 hours
Evaluate the effect of MSA-2 and MSA-2-Pt on the viability of MC38 cells. The results showed that MSA-2-Pt induced cell death significantly from 75 μM, showing a dose-dependent response, while MSA-2 did not cause cell death until 300 μM.
ACS Omega. 2024 Jan 3;9(2):2650-2656.
RAW264.7 cells
10, 25, 50 µM
3 hours
Evaluate the activation of the STING signaling pathway by MSA-2 and MSA-2-Pt. The results showed that both MSA-2-Pt and MSA-2 increased the levels of phosphorylated P65 (P-P65).
ACS Omega. 2024 Jan 3;9(2):2650-2656.
Mouse bone marrow-derived dendritic cells
10 µM MSA-2
30 min pretreatment followed by 2hours exposure to LLC-conditioned media
To assess the effect of STING agonist MSA-2 on Ch25h mRNA expression, results showed MSA-2 partially prevented tumor-conditioned media-induced downregulation of Ch25h mRNA
Nat Commun. 2022 Nov 4;13(1):6623.
MCF7 cells
35 µM
6 hours
To evaluate the activation of the STING-IFNβ pathway by MSA-2, results showed that MSA-2 significantly increased intracellular pIRF3 abundance.
Nat Commun. 2025 Feb 14;16(1):1629.
A549 cells
35 µM
6 hours
To evaluate the activation of the STING-IFNβ pathway by MSA-2, results showed that MSA-2 significantly increased intracellular pIRF3 abundance.
Nat Commun. 2025 Feb 14;16(1):1629.
CT26 cells
35 µM
6 hours
To evaluate the activation of the STING-IFNβ pathway by MSA-2, results showed that MSA-2 significantly increased intracellular pIRF3 abundance.
Nat Commun. 2025 Feb 14;16(1):1629.
B16F10 cells
35 µM
6 hours
To evaluate the activation of the STING-IFNβ pathway by MSA-2, results showed that MSA-2 significantly increased intracellular pIRF3 abundance.
Nat Commun. 2025 Feb 14;16(1):1629.
MSA-2 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB/c mice
Metastatic dormancy model of breast cancer
Intraperitoneal injection
1 mg per dose
Single dose, 7 days post-inoculation
To evaluate the effect of MSA-2 on breast cancer metastatic dormancy, results showed a single dose significantly prolonged mouse survival time
Cancer Res. 2024 Oct 15;84(20):3337-3353.
Mice
Bilateral 4T1 tumor-bearing mice model
Intravenous injection
10 mg/kg
Single injection, observed for 21 days
Evaluated the inhibitory effect of AMFL on primary and distant tumors, showing that AMFL+NIR treatment significantly suppressed primary tumor growth and controlled distant tumor growth, improving survival rates.
J Am Chem Soc. 2025 Mar 5;147(9):7433-7444
C57BL/6 mice
MC38 colon carcinoma model and B16F10 melanoma model
Intratumoral injection
150 μg
Three doses
Evaluate the antitumor effect of MSA-2-Pt in MC38 and B16F10 tumor models. The results showed that MSA-2-Pt significantly reduced tumor growth and increased survival, with 7/9 mice tumor-free in the MC38 model and 2/10 mice tumor-free in the B16F10 model.
ACS Omega. 2024 Jan 3;9(2):2650-2656.
BALB/c mice
4T1 breast cancer model
Intravenous injection
2.4 mg/kg
Every 2 days for a total of 3 times
To evaluate the antitumor effect and immune activation of MSA-2 in vivo, results showed that MN NPs significantly inhibited tumor growth and promoted DC maturation and T-cell infiltration.
Biomater Res. 2024 Jul 4;28:0048
FVB mice
EGFR-mutant lung cancer model
Intraperitoneal injection
20 mg/kg
Every three days
Evaluate the effect of MSA-2 combined with osimertinib
Front Immunol. 2023 Feb 16;14:1077203
C57BL/6 mice
B16F10 tumor model
Orthotopic implantation
22.5 mg/kg
Single implantation, observed for 48 hours
To evaluate the antitumor immune response of MSA-2 in vivo, results showed that MSA-2 significantly increased intratumor levels of IFNβ and IFNγ, and promoted DC maturation and T cell infiltration.
Nat Commun. 2025 Feb 14;16(1):1629.
C57BL/6 mice
Subcutaneous MC38 colorectal tumor model
Intravenous injection
35 mg/kg
Administered on days 0, 4, and 8, total of 3 doses
To evaluate the antitumor efficacy of SAProsomes, results showed SAProsome-3 significantly inhibited tumor growth and induced 100% complete response rate.
To evaluate the anti-tumor efficacy of MSA-2 combined with anti-PD-1 therapy, results showed the combination significantly inhibited tumor growth and improved survival, which was dependent on CH25H expression
Nat Commun. 2022 Nov 4;13(1):6623.
Mice
B16, EMT-6, CT26, and H22 models
Oral
50 mg/kg
Single dose
To evaluate the antitumor activity of MSA-2 combined with YM101, results showed the combination therapy significantly inhibited tumor growth and prolonged mouse survival.
J Hematol Oncol. 2022 Oct 8;15(1):142.
Mice
U14 and TC-1 cervical cancer models
Oral
50 mg/kg
Single dose
To evaluate the inhibitory effect of MSA-2 alone or in combination with anti-PD-1 on the growth of subcutaneous cervical tumors. Results showed that MSA-2 significantly suppressed tumor growth and had a better effect when combined with anti-PD-1.
Front Immunol. 2024 Mar 14;15:1342647
Mice
B16F10 melanoma model
Intratumoral injection
500 µg/dose
Administered on days 1, 4, and 7
Evaluate the in vivo antitumor effect of DW18343, results showed DW18343 significantly inhibited tumor growth.
MedComm (2020). 2024 Dec 20;6(1):e70001
C57BL/6 mice
Pan02 pancreatic cancer model
Intravenous injection
every 2 days for 16 days
Every 2 days for 16 days
Evaluate the in vivo antitumor activity of MSA-2 and cisplatin conjugates, showing significant tumor growth inhibition and enhanced immune response.
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