The expression of programed death ligand 1 (PD-L1) in tumors and its microenvironment is influenced by a variety of factors. The presence of PD-L1 in the triple-negative breast cancer (TNBC) and stromal cells has provided us an opportunity to employ therapeutic monoclonal antibodies targeting PD-L1, though the success rate is low (20–40%). This may be due to innate or acquired resistance to anti-PD-L1 therapies. By judiciously selecting immunohistochemical assays for the detection of PD-L1 in tumor biopsies, one may select patients more appropriately for anti-PD-L1 or anti-PD-1 therapies. In addition, therapies targeting other immune checkpoints, such as PD-L2 and T lymphocyte immunoreceptor with Ig and ITIM domains (TIGIT), must be considered. Furthermore, adding an arm of targeted therapy or neoadjuvant chemotherapy (NACT) to the PD-L1/TIGIT joint immunotherapy platform may offer better therapeutic control over primary tumor progression and metastasis in TNBC. An optimal combination therapy may achieve an efficacious and durable therapy response with minimal toxicity. The overall goal is to improve the quality of life and extend life expectancy in metastatic TNBC patients.