Integrin α2 (CD49b) blockade remodels the tumor immune microenvironment and enhances anti-PD-L1 therapy in 4T1 breast...

Collagen is a defining feature of breast tumors and is increasingly recognized as a regulator of tumor progression and immune exclusion. However, the tumor cell-matrix interaction that link collagen sensing to immune suppression remains poorly understood.

The primary objective of this study was to identify the role of integrin α2 (CD49b/ITGA2) in promoting collagen-dependent tumor growth and immune evasion in breast cancer.

Integrated bulk and single cell transcriptomic analyses reveal that ITGA2 is broadly expressed across breast cancer subtypes and is preferentially localized to malignant epithelial cells. Functional assays demonstrate that CD49b is a dominant receptor mediating breast cancer cell adhesion to collagen I and IV. Genetic ablation or antibody-mediated blockade of CD49b suppresses tumor growth in vivo and profoundly remodels the tumor immune microenvironment, characterized by increased infiltration of CD8⁺ T cells and antigen-presenting dendritic cell subsets, alongside reduced immunosuppressive myeloid populations. Consistent with these findings, ITGA2 expression in human breast cancer cohorts correlates with stromal enrichment and immune exclusion signatures. Importantly, CD49b blockade synergizes with PD-L1 immune checkpoint inhibition, enhancing T cell activation, effector function, and tumor control.

Together, these results identify CD49b mediated tumor collagen interactions as a key driver of immune suppression and resistance to immunotherapy, and provide a mechanistic rationale for targeting integrin α2β1 to enhance antitumor immunity in the 4T1 breast cancer model.