Breast cancer (BC) comprises the most prevalent malignancy among females, whilst being the chief cause of cancer-related mortalities. The advent of immunotherapy has opened the gateway towards several therapeutic strategies that surpass the conventional approaches with regards to efficacy and specificity. The most prominent of said strategies is immune checkpoint inhibitors (ICI), which despite its promise has shown evidence of primary and secondary resistance. It has been suggested that the BC-induced immune suppressive tumor microenvironment (TME) can be a definite reason for ICI resistance. As such, we aim to investigate the possible mechanisms of resistance related to TME and probe the administration of a toxicologically safe anti-cancer natural compound known as quercetin-3′-methoxy-3-O-(4″-acetylrhamnoside)-7-O-α-rhamnoside isolated by our group from Cleome droserifolia to alleviate the immune suppressive nature of BC-TME.