Objectives Investigating the mechanism of β-2 microglobulin (B2M) gene in breast cancer progression and resistance to PD-L1 inhibitors.Methods Initially, a comprehensive analysis was performed to examine the correlation between B2M and CD274, followed by the generation of an immune cell infiltration map. Subsequently, a B2M knockdown (B2M KD) 4T1 cell line was developed to assess the influence of B2M expression on PD-L1 levels and cellular functions. Finally, a subcutaneous tumor model was established and subjected to treatment with a PD-L1 inhibitor to evaluate its effects on immune cell infiltration and mechanisms of therapeutic resistance.Results We discovered the elevated levels of B2M and PD-L1 in breast cancer, which are associated with increased immune cell infiltration. Our findings demonstrated that B2M KD in 4T1 cells led to reduced proliferation, accompanied by enhanced apoptosis. Notably, B2M KD in 4T1 cells resulted in decreased levels of PD-L1. PD-L1 enhanced 4T1 cells proliferation, invasion, and migration while inhibiting apoptosis, similar to the functions of B2M gene. Interestingly, our vivo experiments revealed that B2M KD mice groups exhibited suppressed tumor weight and volume, and ineffectiveness upon PD-L1 inhibitors treatment.Conclusion Our study revealed that B2M gene knockdown may impair breast cancer cell proliferation and confer resistance to PD-L1 inhibitors by decreasing both immune cell recruitment and PD-L1 expression, thereby providing a novel insight for clinical therapy of breast cancer.