In-situ clickable prodrug nanoplatform locally activates T lymphocytes to potentiate cancer immunotherapy

The immune-excluded tumors (IETs) respond marginally to current immune blockade therapy due to the presence of pathophysiological barriers to restrict intratumoral infiltration of the cytotoxic T lymphocytes (CTLs). In this study, to improve the immunotherapy of the IETs, we proposed an in-situ clickable prodrug nanoplatform composed of two sets of acidity-activatable nanoparticles (NPs) for combinatory treatment. The first set of the NPs, namely precursor NPs, could be activated with the extracellular tumor acidity to label tumor extracellular milieu with dibenzocyclooctyne (DBCO) and indocyanine green, which performed florescence imaging-guided photothermal ablation of the extracellular matrix, thereby recruiting the tumor-infiltrating CTLs. The second set of NPs (i.e., the secondary NPs) were functionalized with azide groups, and specifically accumulated at the tumor site via bioorthogonal click reaction with DBCO. The secondary NPs were deshelled with matrix metalloproteinase-2 and activated in the endocytic acidic mi-croenvironment for intracellular release of the BRD4 inhibitor JQ1. Sequential administration of the pre -cursor and the secondary NPs, effectively promoted intratumoral infiltration of CTLs, suppressed PD-L1 upregulation, and was effective for regression 4T1 breast tumor growth, a model of the IETs. This study utilizing the tumor microenvironment-activatable in-situ click chemistry might provide an unprecedented modality to potentiate immunotherapy of the IETs.(c) 2022 Elsevier Ltd. All rights reserved.

Automated summary

Due to pathophysiological barriers, the immune-excluded tumors (IETs) have limited response to current immune blockade therapy. In this study, a clickable prodrug nanoplatform was proposed to enhance immunotherapy of IETs by improving intratumoral infiltration of cytotoxic T lymphocytes (CTLs). The nanoplatform consisted of acidity-activatable nanoparticles and sequentially activated in the tumor microenvironment to promote the regression of IETs.