Reversing the immunosuppressive tumor microenvironment via "Kynurenine starvation therapy" for postsurgical triple-negative breast cancer treatment.

Immunotherapy is a potential strategy to suppress the postoperative recurrence and metastasis of triple-negative breast cancer (TNBC). However, the excessive accumulation of kynurenine (Kyn) leads to immunosuppressive tumor microenvironment (TME) and impedes immunotherapeutic efficacy. Herein, a two-pronged approach through "Kynurenine Starvation Therapy" is proposed based on the in-situ hydrogel implantation for postsurgical treatment of TNBC. The hydrogel is constructed via Schiff base reaction between oxidized dextran (ODEX) and 8-arm poly(ethylene glycol) amine (8-arm PEG-NH2), which exhibits excellent biocompatibility and gradual biodegradability. The indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor NLG919 and kynureninase (KYNase) are noncovalently loaded into the hydrogel to prepare NLG919 + KYNase@Gel. The obtained hydrogel can sustainably release NLG919 and KYNase to synergistically deplete Kyn, thereby reversing immunosuppression to enhance the antitumor immunity within TME through "Kynurenine Starvation Therapy". Moreover, a single implantation of NLG919 + KYNase@Gel not only effectively inhibits the postoperative recurrence and metastasis in 4 T1 tumor-bearing mice, but also restrains the growth in an orthotopic TNBC mouse model. These findings highlight an innovative strategy to reinforce the antitumor immune response for the treatment of postsurgical TNBC.