Songnan Wang

All Publications

• ENPP1 inhibitor with ultralong drug-target residence time as an innate immune checkpoint blockade cancer therapy. Cell reports. Medicine Wang, S., Johnson, R. M., Carozza, J. A., Fernandez, D., Scicinski, J., Verity, N. A., Mardjuki, R., Cao, X., Guo, Y., Papkoff, J., Ray, N., Li, L. 2025: 102336

  Abstract

  Only one in five patients respond to immune checkpoint inhibitors, which primarily target adaptive immunity. Ectonucleotide pyrophosphatase/phophodiesterase 1 (ENPP1), the dominant hydrolase of 2'3'-cyclic-GMP-AMP (cGAMP) that suppresses downstream stimulator of interferon genes (STING) signaling, has emerged as a promising innate immunotherapy target. However, existing ENPP1 inhibitors have been optimized for prolonged systemic residence time rather than effective target inhibition within tumors. Here, we report the characterization of STF-1623, a highly potent ENPP1 inhibitor with an exceptionally long tumor residence time despite rapid systemic clearance, enabled by its high ENPP1 binding affinity and slow dissociation rate. We show that membrane-bound ENPP1 on tumor cells, not the abundant soluble ENPP1 in serum, drives tumor progression. Consequently, STF-1623 unleashes anti-tumor immunity to produce robust anti-tumor and anti-metastatic effects across multiple tumor models. Conceptually, this work establishes a noncovalent small-molecule inhibitor of ENPP1 with ultralong drug-target engagement as a safe and precise strategy to activate STING within tumors.

  View details for DOI 10.1016/j.xcrm.2025.102336

  View details for PubMedID 40914167

• A 17-Year Experience of Valvular Heart Surgery in Rwanda. The Annals of thoracic surgery Musoni, M., Wang, S., Schulick, N., Kabano, B., Mukeshimana, G., Mucumbitsi, J., Rusingiza, E., Worrall, N., Goldberg, H., Stewart, K., Nicholson, I., Patton-Bolman, C., Bolman, R., Swain, J., Ntaganda, E., Lin, Y. 2025

  Abstract

  The advanced presentation of rheumatic heart disease in Rwanda often necessitates surgical intervention. We summarize the outcomes of valvular heart surgeries in Rwanda between 2006 and 2023.366 patients in the Rwandan cardiac surgery registry who underwent valvular surgery were included in this study. We examined surgical details, perioperative outcomes, and long-term outcomes. Cox multivariable analyses were conducted to assess factors predictive of survival outcomes. Additionally, subgroup analyses compared outcomes between mechanical valve replacement and bioprosthetic valve replacement.The average age at surgery was 25.0±10.2 years, with the majority being female (63.9%). Mitral valve surgery, either alone (45.9%) or in conjunction with tricuspid valve surgery (20.8%), was the most common procedure (66.7%). The 30-day postoperative mortality rate was 2.2%. Over an average follow-up of 7.8±4.5 years, the all-cause mortality rate was 18.2%. Patients who received a bioprosthetic valve replacement had a higher all-cause mortality rate than those who received a mechanical valve replacement (32.7% vs. 15.6%, P=0.008). The most common long-term complications for mechanical valve patients were embolism and bleeding (13.0%), compared to structural valve deterioration (26.5%) in bioprosthetic valve patients.The low 30-day mortality rate reflects success in careful patient selection, meticulous surgery, and dedicated perioperative care. Mechanical valve replacement demonstrated superior long-term survival over bioprosthetic valve replacement mainly due to valve degeneration and need for reoperation in bioprosthetic patients. Key areas of improvement include strengthening postoperative follow-up and capacity for increased surgical complexity.

  View details for DOI 10.1016/j.athoracsur.2025.06.008

  View details for PubMedID 40550320

• Cost-Effectiveness Analysis of Surgical Strategies Versus Medical Management for Rheumatic Heart Disease in Rwanda. Journal of the American Heart Association Mlambo, V., Wang, S., Musoni, M., Rando, H., Ingabire, L., Patton-Bolman, C., Mukeshimana, G., Ntaganda, E., Bolman, R., Bendavid, E., Lin, Y. 2025: e038365

  Abstract

  BACKGROUND: One-third of the global rheumatic heart disease burden lies in sub-Saharan Africa, where 17% of patients with severe rheumatic heart disease die within 3years without valve surgery. Surgery is often considered uneconomical, although this assumption is not grounded in cost-effectiveness analyses.METHODS: We evaluated the cost-effectiveness of mechanical valve replacement, bioprosthetic valve replacement, and valve repair compared with medical management for patients with severe rheumatic heart disease in Rwanda. Using a Markov model, we simulated disease progression, incorporating transition probabilities from a meta-analysis of regional observational studies. Costs were calculated using microcosting, and health effects were measured in disability-adjusted life-years (DALYs). Cost-effectiveness was defined by a willingness-to-pay threshold of United States dollars (USD) $2307 per DALY, which is 3 times Rwanda's gross domestic product per capita. A 3% discount rate for costs and DALYs was applied.RESULTS: Surgical strategies extended life expectancy from 7 to 11 to 13years. Mechanical and bioprosthetic valve replacements were cost-effective compared with medical management. Mechanical valve replacement was most efficient, averting 5.64 discounted DALYs for a lifetime discounted cost of USD $10 539.34, with an incremental cost-effectiveness ratio of USD $1704 per DALY. Bioprosthetic valve replacement averted 5.27 discounted DALYs but incurred higher costs (USD $10 873.06). Valve repair only averted 3.30 DALYs despite being least expensive (USD $8790.19). Repair became the most efficient surgical strategy if valve degeneration rates dropped <3.7% annually.CONCLUSIONS: Mechanical valve replacement is the most efficient surgical strategy for severe rheumatic heart disease in sub-Saharan Africa, challenging assumptions that surgery is uneconomical. Reducing surgery costs and optimizing anticoagulation could further enhance cost-effectiveness.

  View details for DOI 10.1161/JAHA.124.038365

  View details for PubMedID 40417784

• ENPP1 inhibitor with ultralong drug-target residence time as an innate immune checkpoint blockade cancer therapy. bioRxiv : the preprint server for biology Johnson, R. M., Wang, S., Carozza, J. A., Fernandez, D., Scicinski, J., Verity, N. A., Mardjuki, R., Cao, X., Papkoff, J., Ray, N., Li, L. 2025

  Abstract

  Only one in five patients is estimated to respond to immune checkpoint inhibitors, which primarily target adaptive immunity. To date, no FDA-approved immunotherapies directly activate the innate anti-cancer immunity-an essential driver of lymphocyte recruitment and potentiator of responses to existing cancer immunotherapies. ENPP1, the dominant hydrolase that degrades extracellular cGAMP and suppresses downstream STING-mediated innate immune signaling, has emerged as a promising therapeutic target. However, existing ENPP1 inhibitors have been optimized for prolonged systemic residence time rather than effective target inhibition within tumors. Here, we report the characterization of STF-1623, a highly potent ENPP1 inhibitor with an exceptionally long tumor residence time despite rapid systemic clearance, enabled by its high ENPP1 binding affinity and slow dissociation rate. We show that membrane-bound ENPP1 on tumor cells, not the abundant soluble ENPP1 in serum, drives tumor progression. Consequently, STF-1623 unleashes anti-tumor immunity and synergizes with ionizing radiation, anti-PD-L1 and anti-PD-1, and a DNA damaging agent to produce robust anti-tumor and anti-metastatic effects across multiple syngeneic mouse tumor models, all without detectable toxicity. Conceptually, this work establishes that a noncovalent small molecule inhibitor of ENPP1 with ultralong drug-target engagement offers a safe and precise strategy to activate STING within tumors, fulfilling an unmet need of innate immunotherapies in cancer.

  View details for DOI 10.1101/2025.05.18.654655

  View details for PubMedID 40475652

  View details for PubMedCentralID PMC12139726

• 2-5A is an immunotransmitter that fuels RNase L immunity. Immunity Wang, S., Li, L. 2025; 58 (4): 770-772

  Abstract

  cGAS-cGAMP-STING and OAS-2-5A-RNase L are evolutionarily convergent innate immune pathways. cGAMP acts as an immunotransmitter; what about 2-5A? In this issue of Immunity, Huai etal. map the transfer of 2-5A between cells, establishing it as a bona fide immunotransmitter.

  View details for DOI 10.1016/j.immuni.2025.03.007

  View details for PubMedID 40203803

• Pilot Implementation of a Simulation-Based Surgical Curriculum for Rwandan Medical Interns. Journal of surgical education Kirsch, M., Mpirimbanyi, C., Wang, S., Kansayisa, G., Gasakure, M., Ntirenganya, F., Lin, Y. 2025; 82 (5): 103475

  Abstract

  Develop and implement a standardized surgical training curriculum for Rwandan medical interns to better prepare them for general practice at district hospitals. Assess the curriculum's impact on participants surgical knowledge and technical skills and identify areas for iterative improvement.A 2-day surgical curriculum combining theory-based didactics and hands-on, simulation-based skills training was developed and implemented. Rwandan medical interns were surveyed before and after participation to evaluate their comfort with various core surgical topics and skills.The study was conducted in Kigali, Rwanda.35 participated, Rwandan medical interns who had completed or were completing their surgical rotations were enrolled in the study.Significant improvements were observed in participants' confidence in both surgical knowledge and techniques after completing the curriculum. Participants identified simulation as a valuable training technique but reported barriers such as limited access to simulation resources. Most participants reported that the curriculum was beneficial, realistic, and something they would recommend to others.Rwanda faces a shortage of surgical specialists necessitating an expanded scope of practice for general practitioners, including performing common surgical procedures. Our pilot surgical skills curriculum for Rwandan interns demonstrates potential in addressing this need. Future iterations will refine the curriculum and expand its implementation to all Rwandan medical interns to enhance the surgical care that they will provide as general practitioners.

  View details for DOI 10.1016/j.jsurg.2025.103475

  View details for PubMedID 40073675

• Cost-effectiveness analysis of valvular surgery in high- and low- to middle-income countries: A scoping review. World journal of surgery Mlambo, V., Hyles, K., Wang, S., Lin, Y. 2024

  Abstract

  Global disparities in valvular surgery services exist. Cost-effectiveness analysis (CEA) and cost-utility analysis can be used to guide national investment decisions. This scoping review aims to synthesize economic evaluations for valvular surgery by income settings and provide recommendations.A systematic literature review identified primary CEAs or CUAs in English comparing surgical management strategies for valvular heart disease. MEDLINE, Embase, CINAHL, Web of Science, and Business Source Complete were searched using keywords "valvular surgery," "valve disease," "cost-effectiveness," and "cost-benefit analysis". Articles comparing outcomes or costs only were excluded. Search results were uploaded and screened on COVIDENCE. Variables from eligible articles were charted in a spreadsheet.Twenty articles were eligible, six from low- and middle-income countries (LMICs) and 14 from high-income countries (HICs). In HICs, the top conditions were degenerative aortic valve disease (7/14) and mitral valve disease (4/14) compared to congenital (2/6) and rheumatic heart diseases (2/6) in LMICs. HICs evaluated new technologies and techniques, whereas LMICs compared different valve types or surgery versus no intervention. Most articles used published studies (12/20) or databases (7/20) to conduct their CEA and quality-adjusted life years was the most common effectiveness measure (12/20). Comparator interventions were cost-effective in all LMIC articles and in 8/14 for HICs.Economic evaluations are mostly conducted in HICs and for adult conditions. More analyses in LMICs are needed. This can be facilitated by maintaining databases, documenting costs, and implementing quality of life assessments.

  View details for DOI 10.1002/wjs.12381

  View details for PubMedID 39428550

• Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint. Cell reports Mardjuki, R., Wang, S., Carozza, J., Zirak, B., Subramanyam, V., Abhiraman, G., Lyu, X., Goodarzi, H., Li, L. 2024: 114209

  Abstract

  2'3'-Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) is a second messenger synthesized upon detection of cytosolic double-stranded DNA (dsDNA) and passed between cells to facilitate downstream immune signaling. Ectonucleotide pyrophosphatase phosphodiesterase I (ENPP1), an extracellular enzyme, was the only metazoan hydrolase known to regulate cGAMP levels to dampen anti-cancer immunity. Here, we uncover ENPP3 as the second and likely the only other metazoan cGAMP hydrolase under homeostatic conditions. ENPP3 has a tissue expression pattern distinct from ENPP1's and accounts for all cGAMP hydrolysis activity in ENPP1-deficient mice. Importantly, we also show that, as with ENPP1, selectively abolishing ENPP3's cGAMP hydrolysis activity results in diminished cancer growth and metastasis of certain tumor types in a stimulator of interferon genes (STING)-dependent manner. Both ENPP1 and ENPP3 are extracellular enzymes, suggesting the dominant role that extracellular cGAMP must play as a mediator of cell-cell innate immune communication. Our work demonstrates that ENPP1 and ENPP3 non-redundantly dampen extracellular cGAMP-STING signaling, pointing to ENPP3 as a target for cancer immunotherapy.

  View details for DOI 10.1016/j.celrep.2024.114209

  View details for PubMedID 38749434

• ENPP1 is an innate immune checkpoint of the anticancer cGAMP-STING pathway in breast cancer. Proceedings of the National Academy of Sciences of the United States of America Wang, S., Böhnert, V., Joseph, A. J., Sudaryo, V., Skariah, G., Swinderman, J. T., Yu, F. B., Subramanyam, V., Wolf, D. M., Lyu, X., Gilbert, L. A., Van't Veer, L. J., Goodarzi, H., Li, L. 2023; 120 (52): e2313693120

  Abstract

  Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer stimulator of interferon genes (STING) pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single-cell RNA-seq, we show that ENPP1 in both cancer and normal tissues drives primary breast tumor growth and metastasis by dampening extracellular 2'3'-cyclic-GMP-AMP (cGAMP)-STING-mediated antitumoral immunity. ENPP1 loss-of-function in both cancer cells and normal tissues slowed primary tumor growth and abolished metastasis. Selectively abolishing the cGAMP hydrolysis activity of ENPP1 phenocopied ENPP1 knockout in a STING-dependent manner, demonstrating that restoration of paracrine cGAMP-STING signaling is the dominant anti-cancer mechanism of ENPP1 inhibition. Finally, ENPP1 expression in breast tumors deterministically predicated whether patients would remain free of distant metastasis after pembrolizumab (anti-PD-1) treatment followed by surgery. Altogether, ENPP1 blockade represents a strategy to exploit cancer-produced extracellular cGAMP for controlled local activation of STING and is therefore a promising therapeutic approach against breast cancer.

  View details for DOI 10.1073/pnas.2313693120

  View details for PubMedID 38117852

• ENPP1 is an innate immune checkpoint of the anticancer cGAMP-STING pathway. bioRxiv : the preprint server for biology Wang, S., Böhnert, V., Joseph, A. J., Sudaryo, V., Swinderman, J., Yu, F. B., Lyu, X., Skariah, G., Subramanyam, V., Gilbert, L. A., Goodarzi, H., Lingyin, L. 2023

  Abstract

  ENPP1 expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer STING pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single cell RNA-seq (scRNA-seq), we show that ENPP1 overexpression drives primary breast tumor growth and metastasis by synergistically dampening extracellular cGAMP-STING mediated antitumoral immunity and activating immunosuppressive extracellular adenosine (eADO) signaling. In addition to cancer cells, stromal and immune cells in the tumor microenvironment (TME) also express ENPP1 that restrains their response to tumor-derived cGAMP. Enpp1 loss-of-function in both cancer cells and normal tissues slowed primary tumor initiation and growth and prevented metastasis in an extracellular cGAMP- and STING-dependent manner. Selectively abolishing the cGAMP hydrolysis activity of ENPP1 phenocopied total ENPP1 knockout, demonstrating that restoration of paracrine cGAMP-STING signaling is the dominant anti-cancer mechanism of ENPP1 inhibition. Strikingly, we find that breast cancer patients with low ENPP1 expression have significantly higher immune infiltration and improved response to therapeutics impacting cancer immunity upstream or downstream of the cGAMP-STING pathway, like PARP inhibitors and anti-PD1. Altogether, selective inhibition of ENPP1's cGAMP hydrolase activity alleviates an innate immune checkpoint to boost cancer immunity and is therefore a promising therapeutic approach against breast cancer that may synergize with other cancer immunotherapies.

  View details for DOI 10.1101/2023.06.01.543353

  View details for PubMedID 37333273

  View details for PubMedCentralID PMC10274658

• Critical Roles of Translation Initiation and RNA Uridylation in Endogenous Retroviral Expression and Neural Differentiation in Pluripotent Stem Cells. Cell reports Takahashi, K., Jeong, D., Wang, S., Narita, M., Jin, X., Iwasaki, M., Perli, S. D., Conklin, B. R., Yamanaka, S. 2020; 31 (9): 107715

  Abstract

  Previous studies have suggested that the loss of the translation initiation factor eIF4G1 homolog NAT1 induces excessive self-renewability of naive pluripotent stem cells (PSCs); yet the role of NAT1 in the self-renewal and differentiation of primed PSCs is still unclear. Here, we generate a conditional knockout of NAT1 in primed PSCs and use the cells for the functional analyses of NAT1. Our results show that NAT1 is required for the self-renewal and neural differentiation of primed PSCs. In contrast, NAT1 deficiency in naive pluripotency attenuates the differentiation to all cell types. We also find that NAT1 is involved in efficient protein expression of an RNA uridyltransferase, TUT7. TUT7 is involved in the neural differentiation of primed PSCs via the regulation of human endogenous retrovirus accumulation. These data demonstrate the essential roles of NAT1 and TUT7 in the precise transition of stem cell fate.

  View details for DOI 10.1016/j.celrep.2020.107715

  View details for PubMedID 32492424

  View details for PubMedCentralID PMC8195978

• Hypoxia and matrix viscoelasticity sequentially regulate endothelial progenitor cluster-based vasculogenesis. Science advances Blatchley, M. R., Hall, F., Wang, S., Pruitt, H. C., Gerecht, S. 2019; 5 (3): eaau7518

  Abstract

  Vascular morphogenesis is the formation of endothelial lumenized networks. Cluster-based vasculogenesis of endothelial progenitor cells (EPCs) has been observed in animal models, but the underlying mechanism is unknown. Here, using O2-controllabe hydrogels, we unveil the mechanism by which hypoxia, co-jointly with matrix viscoelasticity, induces EPC vasculogenesis. When EPCs are subjected to a 3D hypoxic gradient ranging from <2 to 5%, they rapidly produce reactive oxygen species that up-regulate proteases, most notably MMP-1, which degrade the surrounding extracellular matrix. EPC clusters form and expand as the matrix degrades. Cell-cell interactions, including those mediated by VE-cadherin, integrin-β2, and ICAM-1, stabilize the clusters. Subsequently, EPC sprouting into the stiffer, intact matrix leads to vascular network formation. In vivo examination further corroborated hypoxia-driven clustering of EPCs. Overall, this is the first description of how hypoxia mediates cluster-based vasculogenesis, advancing our understanding toward regulating vascular development as well as postnatal vasculogenesis in regeneration and tumorigenesis.

  View details for DOI 10.1126/sciadv.aau7518

  View details for PubMedID 30906859

  View details for PubMedCentralID PMC6426463

• Modulator Effects on the Water-Based Synthesis of Zr/Hf Metal-Organic Frameworks: Quantitative Relationship Studies between Modulator, Synthetic Condition, and Performance CRYSTAL GROWTH & DESIGN Hu, Z., Castano, I., Wang, S., Wang, Y., Peng, Y., Qan, Y., Chi, C., Wang, X., Zhao, D. 2016; 16 (4): 2295-2301

  View details for DOI 10.1021/acs.cgd.6b00076

  View details for Web of Science ID 000373747700062

• Transcriptional Landscape of Cardiomyocyte Maturation. Cell reports Uosaki, H., Cahan, P., Lee, D. I., Wang, S., Miyamoto, M., Fernandez, L., Kass, D. A., Kwon, C. 2015; 13 (8): 1705-16

  Abstract

  Decades of progress in developmental cardiology has advanced our understanding of the early aspects of heart development, including cardiomyocyte (CM) differentiation. However, control of the CM maturation that is subsequently required to generate adult myocytes remains elusive. Here, we analyzed over 200 microarray datasets from early embryonic to adult hearts and identified a large number of genes whose expression shifts gradually and continuously during maturation. We generated an atlas of integrated gene expression, biological pathways, transcriptional regulators, and gene regulatory networks (GRNs), which show discrete sets of key transcriptional regulators and pathways activated or suppressed during CM maturation. We developed a GRN-based program named MatStat(CM) that indexes CM maturation status. MatStat(CM) reveals that pluripotent-stem-cell-derived CMs mature early in culture but are arrested at the late embryonic stage with aberrant regulation of key transcription factors. Our study provides a foundation for understanding CM maturation.

  View details for DOI 10.1016/j.celrep.2015.10.032

  View details for PubMedID 26586429

  View details for PubMedCentralID PMC4662925

• Combination of Optimization and Metalated-Ligand Exchange: An Effective Approach to Functionalize UiO-66(Zr) MOFs for CO2 Separation. Chemistry (Weinheim an der Bergstrasse, Germany) Hu, Z., Faucher, S., Zhuo, Y., Sun, Y., Wang, S., Zhao, D. 2015; 21 (48): 17246-55

  Abstract

  The strategy to functionalize water-stable metal-organic frameworks (MOFs) in order to improve their CO2 uptake capacities for efficient CO2 separation remains limited and challenging. We herein present an effective approach to functionalize a prominent water-stable MOF, UiO-66(Zr), by a combination of optimization and metalated-ligand exchange. In particular, by systematic optimization, we have successfully obtained UiO-66(Zr) of the highest BET surface area reported so far (1730 m(2)  g(-1) ). Moreover, it shows a hybrid Type I/IV N2 isotherm at 77 K and a mesopore size of 3.9 nm for the first time. The UiO-66 MOF underwent a metalated-ligand-exchange (MLE) process to yield a series of new UiO-66-type MOFs, among which UiO-66-(COONa)2 -EX and UiO-66-(COOLi)4 -EX MOFs have both enhanced CO2 working capacity and IAST CO2 /N2 selectivity. Our approach has thus suggested an alternative design to achieve water-stable MOFs with high crystallinity and gas uptake for efficient CO2 separation.

  View details for DOI 10.1002/chem.201503078

  View details for PubMedID 26477589