InVivoMAb anti-mouse/human/rat PD-L1

Colorectal cancer immunotherapy remains limited by insufficient innate immune activation, poor tumor immune infiltration, and resistance to immune checkpoint blockade. Herein, we developed a KAT6A inhibitor-loaded and anti-PD-L1-coated manganese metal-organic framework (MnMOF) nanoplatform for enhanced colorectal cancer immunotherapy through coordinated cGAS-STING activation and PD-L1 blockade. The KAT6A inhibitor (Ki) PF-9363 was loaded into MnMOF, followed by surface modification with anti-PD-L1 antibody to obtain Ki@MnMOF@P. The nanoplatform exhibited efficient Ki loading, pH-responsive drug release, and retained PD-L1 blocking activity. In vitro, Ki@MnMOF@P showed enhanced cellular uptake and selective cytotoxicity against HCT116 cells while maintaining low toxicity toward normal colonic epithelial NCM460 cells. In a CT26 colorectal tumor-bearing mouse model, systemic administration of Ki@MnMOF@P significantly inhibited tumor growth, reduced tumor weight, and prolonged survival. Moreover, Ki@MnMOF@P achieved favorable tumor accumulation without obvious systemic toxicity. Mechanistically, Ki@MnMOF@P suppressed KAT6A expression, promoted cGAMP production, enhanced cGAS expression, and increased STING phosphorylation in tumor tissues. Besides, the nanoplatform remodeled the tumor immune microenvironment by elevating IFN-β, CXCL10, TNF-α, IL-6, and IFN-γ levels and increasing CD8+ and CD4+ T-cell infiltration. These findings demonstrate that Ki@MnMOF@P integrates KAT6A inhibitor and manganese-mediated cGAS-STING activation and anti-PD-L1-mediated checkpoint blockade, providing a promising nanomedicine strategy for colorectal cancer immunotherapy.

Cancer-associated fibroblasts (CAFs) are key modulators of tumor growth, the tumor immune context, and treatment response. CAFs take on diverse phenotypes with distinct functions. Myofibroblastic CAFs (myCAFs) regulate extracellular matrix remodeling, while inflammatory CAFs (iCAFs) modulate immune infiltration. Further studies are required to validate biomarkers of CAF phenotypes and to identify means to therapeutically manipulate CAFs.

Hepatocellular carcinoma (HCC) is a common and deadly cancer, often diagnosed at advanced stages, limiting surgical options. Transcatheter arterial chemoembolization (TACE) is a primary treatment for inoperable and involves the use of drug-eluting microspheres to slowly release chemotherapy drugs. However, patient responses to TACE vary, with some experiencing tumor progression and recurrence. Traditional TACE uses agents like oil-based drug emulsions and polyvinyl alcohol particles, which can permanently block blood vessels and increase tumor hypoxia. Additionally, TACE can suppress the immune system by reducing immune cell numbers and function, contributing to poor treatment outcomes. New approaches, like TACE using degradable starch microspheres and hydrogel-based materials, offer the potential to create different tumor environments that could improve both safety and efficacy. In our research, we developed a composite hydrogel (IF@Gel) made of Poloxamer-407 gel and Fe3O4 nanoparticles, loaded with idarubicin, to use as an embolic material for TACE in a rat model of orthotopic HCC. We observed promising therapeutic effects and investigated the impact on the tumor immune microenvironment, focusing on the role of immunogenic cell death (ICD). The composite hydrogel demonstrated excellent potential as an embolic material for TACE, and IF@Gel-based TACE demonstrated significant efficacy in rat HCC. Furthermore, our findings highlight the potential synergistic effects of ICD with anti-PD-L1 therapy, providing new insights into HCC treatment strategies. This study aims to provide improved treatment options for HCC and to deepen our understanding of the mechanisms of TACE and tumor environment regulation.

Aging is a pivotal risk factor for cancer, yet the underlying mechanisms remain poorly defined. Here, we explore age-related changes in the rat mammary gland by single-cell multiomics. Our findings include increased epithelial proliferation, loss of luminal identity, and decreased naive B and T cells with age. We discover a luminal progenitor population unique to old rats with profiles reflecting precancerous changes and identify midkine (Mdk) as a gene upregulated with age and a regulator of age-related luminal progenitors. Midkine treatment of young rats mimics age-related changes via activating PI3K-AKT-SREBF1 pathway and promotes nitroso-N-methylurea-induced mammary tumorigenesis. Midkine levels increase with age in human blood and mammary epithelium, and higher MDK in normal breast tissue is associated with higher breast cancer risk in younger women. Our findings reveal a link between aging and susceptibility to tumor initiation and identify midkine as a mediator of age-dependent increase in breast tumorigenesis.