Background Combinationoftherapeuticmodalitiesthattargetthetumorcellsand immune suppressor cells constitute a promising avenue for controlling primary tumor growthandsuccessfuleradicationofmetastases.Wehypothesizedthatlocaltumor ablation by photodynamic therapy (PDT) with STL-6014 (an RGD-coupled bacteriochlorophyll) synchronized with administration of gemcitabine, an anti myeloid derived suppressor cells agent, should significantly improve survival in 4T1 murine metastatic breast cancer mouse model. Methods 4T1-Luccellsweregraftedinthemammarypad.Sevendayslater,PDT treatment comprised i.v. bolus administration of STL-6014 and tumor illumination at 753 nm at 4h or 6h following STL-6014 administration was performed. Two days before or on the following day and every 5 days till day 30, mice were i.p. injected with gemcitabine(75mg/kgbody).Metastaseswereassessedbyluciferinbioluminescence using IVIS spectrum imaging system. Results FACS and tissue immunohistochemistry analyses showed STL-6014 heterogeneous accumulation in cancer cells, endothelial cells, cancer associated fibroblasts, myeloid-derived suppressor cells, and tumor-associated macrophages. Illumination of the 4T1 tumors 4h post STL-6014 administration resulted in complete ablation of primary tumors in up to 70% of the treated mice. Damage to blood vessels followed by apoptotic and necrotic cell death was detected within 24h post PDT. Regardless of successful primary tumor ablation, > 80% of the treated animals developed lung metastases at day 28. In contrast, when PDT was combined with gemcitabine, ~35% of mice were cured 120 days post PDT, while 35-45% developed local recurrence without metastasis and 20-30% had both. Overall, ~80% of mice in the combinedgroup weremetastases freeatthedayofsacrifice(eitherduetolocal recurrenceorafter120 daysoffollowup). Thecombinedtreatmentblockedsplenic elevation ofMDSC, Tregs andTAMsandincreasedDCandCD8 cellspopulations. Conclusions:Inconclusion, thesignificantsuppressoflungmetastasisandincreasein cancer free survival in mice bearing metastatic 4T1 tumors following combination treatmentprovides novelapproachforthetreatmentoftriplenegativebreastcancer. Legal entity responsible for the study: Weizmann Institute ofScience Funding The Wade Thompson foundation Disclosure All authors have declared no conflicts ofinterest.