The efficacy of immunotherapy against triple-negative breast cancer (TNBC) heavily relies on intratumoral infiltration of cytotoxic T lymphocytes (CTLs). Although neoadjuvant chemotherapy together with immunotherapy has been approved for advanced TNBC, its efficacy is still unsatisfactory possibly due to systemic treatment-induced lymphatic system disorders and upregulation of additional immune checkpoints in the tumors.

In a study published in Nature Communications, a research team led by Prof. LI Yaping from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, and Prof. ZHANG Pengcheng from ShanghaiTech University, designed a novel strategy of local neoadjuvant immunotherapy. 

Researchers created an injectable hydrogel composed of cyclin-dependent kinase 4/6 inhibitor Abemaciclib (Abe)-loaded peptide-NLG919 prodrug nanofibers, namely Abe-NF(g). 

They demonstrated that after a local injection, the hydrogel retained at the tumor site for at least seven days and served as a reservoir of Abe and NLG919, which greatly improved ratio of drugs between tumors and major organs. Improved and prolonged tumor exposure of Abe primed immunogenic cell death of cancer cells, promoted dendritic cells maturation, induced classic macrophage activation, and activated CTLs. Reduced systemic exposure of Abe minimized the incidence of lymphopenia and hepatic toxicity. 

Besides, researchers found that although Abe could upregulate expression of indoleamine 2, 3-dioxygenase 1, the persistently released NLG919 locally inhibited the enzyme activity, limiting the production of kynurenine and activation of regulatory T cells. With a single injection, Abe-NF(g) improved tumor infiltration of active CTLs and generation of effector memory T cells, significantly inhibiting recurrence of TNBCs and pulmonary metastasis.

The findings of this study represent an advancement in local neoadjuvant immunotherapy for TNBC with reduced toxicity. This study shows an injectable hydrogel platform composed of prodrug-based fibrous nanomedicine, which can accommodate additional drugs to achieve synergistic effects.