Background Patients with triple-negative breast cancer (TNBC) are better responders to neoadjuvant chemotherapy; however, they are poor in the durability of response with decreased overall and progression-free survival. Methods Given that significant improvements have been reported with PD-L1-PD-1 blockade in different cancers, we evaluated the in vitro and in vivo effectiveness of Tomivosertib (eFT-508), an anthracycline, adriamycin, and MNK1/2 inhibitor, which has been previously shown to inhibit translation of PD-L1 in mice model of liver cancer, alone or in combination using BC cell lines and an orthotopic xenograft mice model using the TNBC cell line MDA-MB-231. Results Within the context of The Cancer Genome Atlas (TCGA) dataset, expression of CD274 mRNA, which encodes programmed death-ligand 1 (PD-L1), was found to be significantly overexpressed in TNBC patients compared to patients with HER2 + or luminal breast cancer (BC). Even within TNBC sub-types, CD274 expression was significantly higher in the immune modulatory subtype (TNBC-IM). BC cells exhibited high IC50 = 0.85 ± 0.07 nM with Adriamycin and significantly lower IC50 = 0.23 ± 0.04 nM with eFT-508 ( P < 0.01). Combination treatment showed in vitro synergism on chemosensitivity. Combination therapy also exhibited a synergistic effect on inhibition of tumor growth and lung colonization in vivo. Mass cytometry-based evaluation of the tumor microenvironment revealed significant attenuation of both PD-L1 and PD-L2 following mono- or combination therapy with eFT-508. Conclusions Treatment with eFT-508 restored effector and cytotoxic function of tumor-infiltrating CD8 + T cells in mice. The remarkable efficacy observed both in vitro and in vivo, and clinical synergism with adriamycin, highlights the potential of eFT-508 as an alternative, yet more efficacious, therapeutic option for patients with TNBC. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03474-9.