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

Evaluation of 18F-FPPA as a Positron Emission Tomography Radioligand for Imaging CSF1R in LPS-Induced Rat Model of Neuroinflammation. (PubMed, Mol Pharm) - "A decreased uptake also was observed in cold 19F-FPPA, BLZ945, and PLX3397 blocking groups (P 0.05). The in vivo imaging and immunohistochemical results confirmed the specific uptake of 18F-FPPA by targeting CSF1R on microglia in inflamed tissues. Overall, our findings demonstrated that 18F-FPPA had great potential as a promising tracer for the imaging of neuroinflammatory diseases, while its unique binding profile also provides insights into CSF1R-targeted ligand development."

Journal • Preclinical • Gastrointestinal Disorder • Inflammation • CSF1R

FAP⁺ pericyte-like cells drive immunosuppressive macrophage differentiation and myeloid recruitment through paracrine signaling in glioblastoma (EANO 2026) - "CSF1R inhibition (BLZ945) was used to evaluate pathway involvement...FAP⁺ pericyte-like cells promote monocyte recruitment and drive differentiation into immunosuppressive TAM-like macrophages through paracrine signaling, in part mediated by the CSF1/CSF1R axis. Their secretory profile and in vivo effects support a role for this perivascular stromal population in shaping myeloid infiltration and immune suppression in GBM."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CCL2 • CD14 • CD163 • CD80 • CXCL12 • IFNG • MRC1 • PTPRC

Time-staggered chemo-immunotherapy via engineered nanofiber resists postoperative dynamic immunosuppression in glioblastoma. (PubMed, Nat Commun) - "Structurally, the tunable nanofiber composition enables time-staggered release of doxorubicin (DOX) to induce immunogenic cell death and BLZ945 to suppress protumoral macrophage programs and abundance. After surgical resection of orthotopic GL261 tumors, a single implantation achieves 83.9% tumor inhibition and establishes immune memory. This study explores the evolving GBM relapse process to guide engineered nanofiber design with time-staggered drug therapy against postoperative recurrence."

Journal • Brain Cancer • Glioblastoma • Immune Modulation • Immunology • Oncology • Solid Tumor

Targeting macrophages to improve radiotherapy response in brain metastasis (EACR 2026) - "We evaluated RT alone versus RT combined with the CSF-1R inhibitor BLZ945 using tumor progression and survival as primary endpoints, complemented by functional assays to interrogate treatment-associated immune and tumor phenotypes.Result and Preliminary findings show an overall benefit of combining BLZ945 with RT compared with either treatment alone. Following this intriguing result, ongoing research is focused on defining how TAMs shape the response to RT and on identifying mechanisms underlying the responder versus non-responder phenotypes to inform biomarkers and rational combination strategies."

Solid Tumor

Combined treatment of TROP‑2 targeted CAR-T and vascular disruptor CBP enhances anti‑tumor activity in triple‑negative breast cancer. (PubMed, Transl Oncol) - "Our findings demonstrated the potential of TROP-2 as a viable target for CAR-T therapy in breast cancer. The combination of TROP-2 CAR-T cells with CBP not only enhances the therapeutic efficacy but also maintains a favorable safety profile, offering a promising new strategy for the treatment of breast cancer."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • TACSTD2

CSF1R signaling contributes to macrophage-associated CCL11 production and eosinophil recruitment in murine allergic conjunctivitis. (PubMed, Mol Immunol) - "Recombinant CCL11 significantly restored eosinophil infiltration in BLZ945-treated mice, supporting a role for CCL11 as a downstream effector of CSF1R signaling in this model. Collectively, these findings support a contributory role for CSF1R signaling in macrophage-associated eosinophilic inflammation in murine AC and suggest that targeting CSF1R may represent a potential therapeutic strategy for ocular allergic disease."

Journal • Preclinical • Allergy • Conjunctivitis • Inflammation • Ocular Infections • Ocular Inflammation • Ophthalmology • CCL11 • CSF1R • IL34 • MRC1 • PTPRC

Dual stromal and tumoral origins of TWEAK drive CSC maintenance in ovarian cancer relapse (AACR 2026) - "Inhibition of macrophage recruitment using a CSF-R1 inhibitor BLZ945 during chemotherapy significantly reduced CSC expression and improved survival, compared to chemotherapy alone...Future studies will investigate how macrophages regulate OC-derived TWEAK and the contribution of this signaling to relapse. Defining the stromal and tumoral cell sources of TWEAK and delineating their roles in TWEAK-Fn14 mediated tumor recurrence may facilitate development of targeted therapies for patients at risk of recurrence."

Clinical • Stroma • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD31 • CD80 • ITGAM • KIT • LYVE1 • MRC1 • PDGFRA • PD-L2 • PECAM1 • PTPRC • TNFSF12

RUNX1 Directly Activates WNT2 to Orchestrate Tumor-Associated Macrophage Reprogramming in Colorectal Cancer. (PubMed, Mol Carcinog) - "In vivo, we evaluated tumor growth (subcutaneous xenografts) and lung metastasis (tail-vein injection) following WNT2 knockdown and performed rescue studies using an IL-10 neutralizing antibody or the CSF1R inhibitor BLZ945...RUNX1 directly activates WNT2 to promote cytokine production and M2 macrophage polarization, thereby accelerating CRC growth and metastasis. These findings suggest that targeting the RUNX1-WNT2 axis and its downstream macrophage programs may offer a therapeutic strategy and potential biomarker framework for CRC."

Journal • Colorectal Cancer • Oncology • Solid Tumor • Thoracic Cancer • CCL2 • CD20 • CD68 • CD86 • IL10 • MRC1 • RUNX1 • WNT2

Teriflunomide Attenuates Demyelination and Enhances Remyelination in Organotypic Brain Slice Cultures Through Modulation of Glial Cell Dynamics. (PubMed, CNS Neurosci Ther) - "Teriflunomide exerts beneficial effects on myelin preservation and remyelination in an ex vivo demyelination model, potentially through modulation of glial cell dynamics rather than direct effects on oligodendroglial cells."

Journal • CNS Disorders • Multiple Sclerosis • Solid Tumor • MBP

Targeting CSF-1R with BLZ945 results in effective peripheral and tumor immune microenvironment modulation in advanced solid tumors (AACR 2024) - P1/2 | "Given the potential effects of BLZ945 on effector T-cell activity, a combination of BLZ945 with the programmed death 1 (PD-1) inhibitor spartalizumab was investigated in 1) a dose escalation phase I clinical trial with advanced solid tumor patients; and 2) an expansion phase II clinical trial in adult patients with relapsed/refractory glioblastoma (GBM) after standard of care and other lines of therapy (NCT02829723). This suggests that non-mesenchymal GBM, for which PDGFRA is part of the defining signature, are more sensitive to the treatment. DNA-sequencing of these archival samples also revealed mutations in p53 in the tumors with partial responses but no mutations in EGFR or TERT."

IO biomarker • Metastases • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CSF1R • EGFR • PDGFRA • TERT • TP53

Ultrasound-guided nanocomposite hydrogel injection to enhance nerve repair via temporal delivery of a colony-stimulating factor 1 receptor inhibitor. (PubMed, J Control Release) - "In this study, we developed a nanocomposite hydrogel (DNH/PLGA@BLZ) by combining decellularized porcine sciatic nerve hydrogel (DNH) with poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with BLZ945, a colony-stimulating factor 1 receptor (CSF-1R) antagonist currently in clinical trials...The underlying mechanism may involve facilitating inflammation resolution and lowering inflammation levels, particularly during the middle and later stages of healing, thereby promoting nerve regeneration. In summary, this study advances the preclinical development of CSF-1R inhibitors by demonstrating that ultrasound-guided delivery enables precise, temporally adaptable administration, supporting further safety and dose-evaluation studies."

Journal • Inflammation

Dynamics and Impact of Repopulating Microglia Following Oligodendroglial Damage. (PubMed, J Neurochem) - "Since microglial development and survival critically depend on colony-stimulating factor-1 receptor (CSF-1R) signaling, we employed CSF-1R inhibition with BLZ945 to effectively deplete MG...Interestingly, our in vitro results show a close correlation with in vivo findings previously reported and demonstrate the relevance of our model in developing therapies for demyelinating diseases. These findings underscore both the potential and limitations of microglial modulation aimed at eliminating pro-inflammatory profiles and promoting repopulation with pro-regenerative characteristics."

Journal • CNS Disorders • Multiple Sclerosis • Solid Tumor

Lineage Tracing of Repopulating Microglia in the Auditory Brainstem of Mice (ARO 2026) - "We previously showed that pharmacological depletion of microglia in mice from postnatal day P2 with a colony stimulating factor 1 receptor (CSF1R) inhibitor led to impaired synaptic pruning of the calyx of Held in the medial nucleus of the trapezoid body (MNTB), reduced ABR peak amplitudes, and increased ABR peak latencies...Methods : We used a lineage tracing approach by injecting BLZ945, a CSF1R inhibitor, into mice every other day between P2 and P10, then observing microglia or monocyte markers to determine whether the new microglia have characteristics of peripheral monocytes... These findings suggest that a significant proportion of repopulating microglia arise from peripheral monocytes."

Preclinical • CDKN1A

A Tumor Acidity-Driven Transformable Nanomaterial Mediated Activation of Antigen-Presenting Cells for Cancer Photoimmunotherapy. (PubMed, Small Methods) - "In this study, we designed a tumor acidity-driven transformable nanoparticle self-assembly using a drug-conjugated amphiphilic polymer (mPEG-PLA-Ce6), an acidity-sensitive polymer (PAEMA), and the CSF-1R inhibitor, sotuletinib (BLZ-945), by regulating the pKa and ratio of the acidity-sensitive material (denoted as Ce6SNP/B)...Additionally, the acidity-sensitive material PAEMA has the potential to induce dendritic cell maturation. Thereby, the tumor acidity-driven transformable Ce6SNP/B achieved cancer photoimmunotherapy by targeting tumor cells and activating antigen-presenting cell-mediated anti-tumor immune effect."

Journal • Oncology

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

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

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

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