sotuletinib (BLZ-945) / Novartis, BMS - LARVOL DELTA

From borders to brain: determinants of monocyte and BAM access to the microglial niche (SNO 2025) - "Sall1CreERT2/wt; Ai14-lineage tracing showed that microglia repopulation post-BLZ945 originates from residual Sall1⁺ cells...In rapid, microglia-specific depletion, only blood and border-associated macrophages—not skull marrow monocytes—repopulate the niche, revealing tight spatial and temporal constraints on CNS access. These insights redefine the rules of monocyte engraftment in the brain."

Bone Marrow Transplantation • CLEC12A • CX3CR1 • ITGA4

Fructose metabolism is a unique feature of immunosuppressive myeloid cells in brain tumors (SNO 2025) - "Importantly, depleting TAMs using the CSF1R inhibitor sotuletinib or rewiring them to a proinflammatory state using an anti-TIM3 antibody resulted in the loss of lactate production in vivo, confirming that [6,6-2H]-fructose is a unique tracer of immunosuppressive TAMs in gliomas. Collectively, we leverage a mechanistic understanding of fructose metabolism for non-invasive metabolic imaging of TAM-driven immunosuppression in vivo."

Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • HMOX1 • LGALS3 • PD-L1 • TGFB1

A unique microglia subset associated with aggressive α-synucleinopathy uncovered in a rapidly progressive multiple system atrophy cerebellar type model. (PubMed, Neurobiol Dis) - "Upon doxycycline withdrawal at 8 weeks of age, mice developed progressive cerebellar ataxia by 26 weeks and succumbed by 30 weeks...Prophylactic administration of the CSF1R inhibitor BLZ945 exacerbated motor deficits and demyelination, significantly increasing this microglial population. Similarly, MSR1+ and CD68+ microglia/macrophages were observed in early pontocerebellar lesions of six human MSA-C autopsy cases. These findings suggest that this pro-inflammatory microglia subset plays a central role in disease progression and may represent a promising therapeutic target for modifying the course of MSA-C and related synucleinopathies."

IO biomarker • Journal • Ataxia • CNS Disorders • Movement Disorders • Multiple System Atrophy • Solid Tumor • CCL2 • CCL3 • CD68 • IL1B • ITGAM • NFKBIA • TGM2 • TLR2

CSF1-CSF1R signaling mediates tumor cell-macrophage crosstalk and prognosis in ccRCC. (PubMed, Cancer Gene Ther) - "Functional validation was conducted using a ccRCC xenograft mouse model treated with the CSF1R inhibitor Sotuletinib...Importantly, CellChat-based predictions represent potential, rather than definitive, ligand-receptor interactions, and thus require further mechanistic validation. Targeting CSF1R may offer a promising strategy to modulate the immune landscape and improve therapeutic outcomes in ccRCC."

IO biomarker • Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CD163 • CSF1R

MACROPHAGE INHIBITION ENHANCES PERIPHERAL CAR T CELL EXPANSION AND TUMOR CONTROL IN A PATIENT-DERIVED HUMANIZED MODEL OF AUTOLOGOUS CAR T CELL EFFICACY IN PEDIATRIC OSTEOSARCOMA (OS) (CTOS 2025) - "NSG-SGM3 mice were humanized by injection of patient HSCs after busulfan ablation and autologous CAR T cell efficacy was assessed against orthotopic LM7 OS tumors. Macrophage inhibition with the small molecule BLZ945 was assessed in combination with B7-H3 CAR T cells in Hu-pHSC and nonhumanized mice. CD34+ HSCs engrafted into NSG-SGM3 mice with mean peripheral human engraftment of 10% after 8 weeks... Hu-pHSC mice developed from OS patient bone marrow products allow investigation of the effect of the patient's inhibitory immune environment on CAR T cell efficacy. In this model, CAR T cells had limited antitumor activity, as in early phase clinical trials, unless macrophages were depleted. This model improves on standard xenograft models and has the potential to serve as a reliable avatar for modeling immunotherapeutics for OS."

CAR T-Cell Therapy • Clinical • IO biomarker • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CD276 • CD34 • IFNG • IL10 • IL4 • IL6

Engineering a spatiotemporal macrophage circuit via STING phase separation to override immune suppression in pancreatic cancer. (PubMed, Proc Natl Acad Sci U S A) - "This system, MRC1-targeting peptide-M@BLZ945 (PMMB), integrates a colony-stimulating factor 1 receptor (CSF-1R) inhibitor and a STING agonist within a macrophage-mimetic nanostructure, enabling sequential, controlled reprogramming of TAMs...These findings establish spatiotemporal macrophage circuit engineering via STING phase separation as a cross-scale strategy to override PDAC's immune barriers and drive next-generation macrophage-targeted immunotherapy. This study paves the way for rationally designed, precision macrophage modulation strategies in solid tumors."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD8 • CD80 • MRC1 • STING

From borders to brain: determinants of monocyte and BAM access to the microglial niche (WFNOS 2025) - "Sall1CreERT2/wt; Ai14-lineage tracing showed that microglia repopulation post-BLZ945 originates from residual Sall1⁺ cells...In rapid, microglia-specific depletion, only blood and border-associated macrophages—not skull marrow monocytes—repopulate the niche, revealing tight spatial and temporal constraints on CNS access. These insights redefine the rules of monocyte engraftment in the brain."

Bone Marrow Transplantation • CLEC12A • CX3CR1 • ITGA4

Fructose metabolism is a unique feature of immunosuppressive myeloid cells in brain tumors (WFNOS 2025) - "Importantly, depleting TAMs using the CSF1R inhibitor sotuletinib or rewiring them to a proinflammatory state using an anti-TIM3 antibody resulted in the loss of lactate production in vivo, confirming that [6,6-2H]-fructose is a unique tracer of immunosuppressive TAMs in gliomas. Collectively, we leverage a mechanistic understanding of fructose metabolism for non-invasive metabolic imaging of TAM-driven immunosuppression in vivo."

Brain Cancer • Glioblastoma • Glioma • Solid Tumor • HMOX1 • LGALS3 • PD-L1 • TGFB1

Pharmacological CSF1R Inhibition Attenuates LPS-induced Brain Cytokines and Akt Signaling Pathway (Neuroscience 2025) - "In the sustained LPS model, BLZ945 amplified Akt pathway, but did not attenuate LPS-induced cytokines. Thus, our proof-of-concept data show that CSF1-R inhibition has distinct effects on phospho-protein signaling and cytokine expression in acute vs. sustained inflammatory models."

Alzheimer's Disease • CNS Disorders • Dementia • CCL11 • IFNG • IL10 • IL2

Multiparametric MRI assessment of acute neuroinflammation in a murine model of peripheral LPS stimulation. (PubMed, BMC Med Imaging) - "The present findings highlight the potential of non-contrast-enhanced MRI to assess acute neuroinflammation-related changes in several mouse brain areas upon peripheral LPS stimulation. The assessment of multiple parameters provided sufficient sensitivity to detect pharmacological modulation of the neuroinflammatory response elicited by the endotoxin."

Journal • Preclinical • Inflammation

The Influence of Macrophages Within the Tumor Microenvironment on Ovarian Cancer Growth and Response to Therapies (SOHO 2025) - "We also tested BMS777607, a potent inhibitor of RON, c-MET, AXL, and TYRO3 receptor tyrosine kinases, as a candidate for macrophage-targeted therapy...Notably, combination treatment with paclitaxel and BLZ945, a TAM-targeted CSF-1R inhibitor that depleted TAMs, reduced tumor burden and limited regrowth...Our findings underscore the utility of organoid and huPDX models in evaluating immunomodulatory therapies and studying patient-specific variability to inform personalized strategies against TAM-mediated chemoresistance. These models reveal patient-specific responses, aiding personalized strategies to overcome TAM-driven chemoresistance."

Biomarker • Tumor microenvironment • Oncology • Ovarian Cancer • Solid Tumor • AXL • CCL2 • MET

A CSF-1R inhibitor both prevents and treats triple-negative breast cancer brain metastases in hematogenous preclinical models. (PubMed, Clin Exp Metastasis) - No abstract available

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Patient-derived ovarian cancer models demonstrate the influence of tumor-associated macrophages on therapeutic response. (PubMed, Oncoimmunology) - "Furthermore, BMS777607, a receptor tyrosine kinase inhibitor capable of repolarizing M2 macrophages in vitro, reduced organoid viability via a macrophage-dependent mechanism...A TAM-targeted CSF-1 R inhibitor, BLZ945, combined with paclitaxel reduced tumor burden with no regrowth, suggesting that TAMs promote paclitaxel resistance in this model. Our study demonstrates that TAMs influence response to paclitaxel in both patient-derived OC organoids and huPDX. These models are useful for evaluating immunomodulatory therapy effects and could serve as a robust platform for preclinical testing of novel anti-cancer treatments, providing insights into the complex interplay between immune cells and cancer therapeutics."

Journal • Preclinical • Oncology • Ovarian Cancer • Solid Tumor • CSF1

Evaluation of in vivo and in vitro binding property of a novel candidate PET tracer for CSF1R imaging and comparison with two currently-used CSF1R-PET tracers. (PubMed, EJNMMI Radiopharm Chem) - "These results suggest that [11C]FJRD is a potential CSF1R-PET tracer for more sensitive detection of CSF1R, compared to [11C]CPPC and [11C]GW2580. However, the high level off-target binding necessitates further improvements in specificity for CSF1R imaging."

Journal • Preclinical • Oncology • CSF1R

Microglia endotoxin tolerance is retained after enforced repopulation. (PubMed, Brain Behav Immun) - "Here, we investigated whether microglia depletion-repopulation by inhibition of the colony-stimulating factor 1 receptor with BLZ945 reversed LPS-induced endotoxin tolerance in mice...Nonetheless the blunted inflammatory gene response after LPS-preconditioning was retained after a depletion-repopulation cycle. Our study highlights the persistence of endotoxin tolerance in microglia after a depletion-repopulation cycle which might impact the potential effectiveness of strategies targeted at microglia depletion for clinical applications."

Journal • CNS Disorders • Infectious Disease • Inflammation • CSF1R

Evaluation of in-vivo and in-vitro binding property of a novel PET tracer for CSF1R imaging and comparison with two currently-used CSF1R-PET tracers. (PubMed, Res Sq) - "Addition of cold CPPC partially blocked in - vitro [ 11 C]FJRD binding in the various organs with blocking effects from 9 to 67%, and other two CSF1R inhibitors, GW2580 and BLZ945, showed minimal blocking effect, suggesting unignorable off-target binding in these organs. Conclusions These results suggest [ 11 C]FJRD as a potential CSF1R-PET tracer for more sensitively detecting CSF1R compared to [ 11 C]CPPC and [ 11 C]GW2580. However, high-level off-target binding requires further improvement in specificity for CSF1R imaging."

Journal • Preclinical • Oncology • CSF1R

ENHANCING MICROGLIAL TARGETING IN PRECLINICAL DRUG DISCOVERY VIA HUMAN MICROGLIA CHIMERIC MICE (ADPD 2025) - "Endogenous murine microglia were depleted using BLZ945 treatment, after which human microglial precur sors were engrafted... This humanized microglia -engrafted APP knock -in model closely mimics human neuroinflammatory responses and represents a valuable tool for investigating microglial function and therapeutic targets in neurodegenerative diseases. The robust human microglial e ngraftment and amyloid pathology observed underscore the model's potential for preclinical drug development. Ongoing refinements a im to further enhance the utility of this platform, accelerating the discovery of novel therapies that modulate microglial activity and mitigate disease progression."

Preclinical • Alzheimer's Disease • CNS Disorders • Inflammation • CD9 • CSF1 • PTPRC

Discovery of Novel Pyrrolo[2,3-b]pyridine-Based CSF-1R Inhibitors with Demonstrated Efficacy against Patient-Derived Colorectal Cancer Organoids. (PubMed, J Med Chem) - "In this work, a series of novel CSF-1R inhibitors were designed and synthesized through rational molecular hybridization strategy and step by step structural optimization based on PLX3397 and BLZ945. Mechanically, III-1 efficiently repolarized M2-like TAMs into M1-phenotype, and inhibited the proliferation and promoted apoptosis of tumor cells through immunoregulation. More importantly, III-1 showed demonstrated efficacy against patient-derived colorectal cancer organoids and exhibited stronger anticolorectal cancer efficacy in vivo compared to PLX3397, highlighting its potential in the immunotherapy of colorectal cancer."

Journal • Colorectal Cancer • Oncology • Solid Tumor

Repopulating Microglia in the Auditory Brainstem Recapitulate Developmental Properties following Cessation of CSF1R Inhibitor Treatment (ARO 2025) - "After temporary microglial ablation with the CSF1R inhibitor, BLZ945, repopulating microglia reinstate some active characteristics as they rapidly recover damage from their depletion."

CD68 • CX3CR1 • FAP • GFAP

Modulating tumor-associated macrophages through CSF1R inhibition: a potential therapeutic strategy for HNSCC. (PubMed, J Transl Med) - "Targeting TAMs via CSF1R inhibition enhances the therapeutic efficacy of cisplatin in HNSCC. These findings suggest that CSF1R inhibitors hold promise as a component of combination therapy for HNSCC."

Journal • Head and Neck Cancer • Human Papillomavirus Infection • Infectious Disease • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD68 • CD8 • IL10 • MRC1

Ionizable cationic lipid nanoparticles loaded with miRNA-125b/BLZ945 for pancreatic cancer treatment. (PubMed, Biotechnol Appl Biochem) - "(ii) miRNA-125b LNP/BLZ945 LNP attenuated the depleting effect of BLZ945 on macrophages and significantly inhibited macrophage M2 polarization. It could be effectively distributed in tumors and showed good biosafety while exerting antitumor effects, bringing hope to clinical pancreatic tumor patients."

Journal • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

Proguanil inhibits proliferation and migration in glioblastoma development through targeting CSF1R receptor. (PubMed, Cell Signal) - "More importantly, we found that Proguanil's inhibitory effect on U87MG cell growth and migration was positively correlated with CSF1R expression, and this effect diminished following CSF1R knockdown and Proguanil demonstrated synergistic effects with CSF1R-targeting positive drugs (BLZ945 and GW2580). Meanwhile, Proguanil targeted CSF1R to inhibit M2-type polarization of tumor-associated macrophages (TAMs) and their proliferation, thus altering the tumor microenvironment while indirectly suppressing the proliferation and migration of U87MG cells. Taken together, these findings suggest that Proguanil may serve as a promising CSF1R antagonist for GBM treatment."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CCND1 • CDK4 • CDKN1A • CSF1R • MAP2K1 • MMP3 • PTEN

Targeting brain metastasis from triple-negative breast cancer by blocking CSF1R signaling in the tumor microenvironment (EORTC-NCI-AACR 2024) - "Our data have demonstrated the efficacy of BLZ945 on the burden of brain metastases in animal models of TNBC. In addition, our findings support a role for microglia and macrophages in regulating the development of breast cancer brain metastases. Together, these findings provide a potential therapeutic approach for the prevention and/or treatment of brain metastases."

Biomarker • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CSF1R • GFAP • IL1B • IL6 • TNFA

Enhancing Microglial Targeting in Preclinical Drug Discovery via Human Microglia Chimeric Mice (Neuroscience 2024) - "Immunodeficient (RAG2-/-) newborn mice expressing human CSF1 (to enhance human microglia survival) and three familial APP mutations (APPSAA) were depleted of endogenous microglia using BLZ945 treatment and subsequently engrafted with human microglial precursors...Currently efforts are being made to refine the process of generating chimeric pups, aiming to enhance adherence to study protocols. This innovative platform will represent a valuable tool for expediting the development of novel therapeutics aimed at modulating microglial function and mitigating disease progression."

Preclinical • Alzheimer's Disease • CNS Disorders • CD9 • CSF1 • PTPRC

Tracking changes in functionality and morphology of repopulated microglia in young and old mice. (PubMed, J Neuroinflammation) - "A CSRF1R inhibitor (BLZ-945) depleted microglia within 21 days and a number of microglia was fully restored within 7 days, as confirmed by TMEM119 staining and flow cytometry...We demonstrate that with aging some repopulated MG fail to reach the homeostatic phenotype. These differences may contribute to the deterioration of MG protective functions with age."

Journal • Preclinical • Inflammation