Tumor-microenvironment-modulating microspheres to augment tumor-infiltrating lymphocyte therapy against solid tumors.

Tumor-infiltrating lymphocyte (TIL) therapy is a T cell therapy approved for treating solid tumors. However, the dense extracellular matrix (ECM) and immunosuppressive tumor microenvironment (TME) result in limited numbers and activities of initially harvested TILs, further leading to time-consuming preparation processes and suboptimal treatment efficacy. Herein, we develop alginate-based hydrogel microspheres co-loaded with hyaluronidase (HAase) and chemokine CXCL9. With released HAase to degrade the extracellular matrix and CXCL9 to recruit lymphocyte infiltration, such microspheres after intratumoral injection allow effective TME modulation, leading to greatly enhanced TIL numbers in tumors. TILs collected from those pre-treated tumors exhibit not only accelerated ex vivo expansion but also markedly improved activities and anti-exhaustion capacities. Those TILs after re-infusion could significantly inhibit tumor growths and metastases in different tumor models. Our work demonstrates that modulating TME before tumor collection may be an effective and clinically practical approach to boost current TIL therapies.