Combretastatin A4 nanoparticles (CA4-NPs), which notably inhibit tumor growth, were found to cause tumor regrowth due to the intratumoral enrichment of M2-type macrophages after treatment. Since BLZ945, an inhibitor of CSF-1 receptor (CSF-1R), depletes and inhibits the proliferation of M2-type macrophages, it has the potential to relieve the immunosuppressive microenvironment and improve anti-tumor therapy of CA4-NPs. However, CSF-1R exists widely, not only in macrophages, and BLZ945 could cause potential hepatotoxicity. It is necessary to establish a tumor-targeting drug delivery system to reduce the off-target and side effects of BLZ945. In this study, FXIIIa substrate peptide A15 decorated BLZ945 nanoparticles (A15-BLZ-NPs) were developed, in which, BLZ945-poly(d,l-lactide) (BLZ945-PLA), produced by ring-opening polymerization, was encapsulated in poly(ethylene glycol)-poly(d,l-lactide) (PEG5k-PLA5k), and A15 was decorated on the surface PEG segment. A15-BLZ-NPs could crosslink with fibrin through elevated FXIIIa and specifically target intratumoral coagulation spots induced by CA4-NPs. In vivo studies showed that CA4-NPs induced enhanced distribution of BLZ945 in tumors, as the BLZ945 content was 3.75-fold in the CA4-NP + A15-BLZ-NP group compared to that of A15-BLZ-NP single treatment. Meanwhile, compared to the CA4-NP group, the combination treatment significantly reduced the proportion of M2-type macrophages (from 64.4% to 24.5%) and enriched cytotoxic T lymphocytes (from 1.5% to 18.9%) in tumors, suggesting that A15-BLZ-NPs remodeled and activated tumor immunity after CA4-NP treatment. Furthermore, the combined treatment effectively improved the tumor inhibition rate to 73.4%, which was significantly higher than that of CA4-NP (15.5%) or A15-BLZ-NP (23.9%) single treatment. This work established a novel combination strategy for anti-tumor therapy.