01
Baoxiang Chen, et al.
Adv Sci. 2024.
The RNA modification 5-methylcytosine (m5C) has recently garnered significant attention as a critical post-transcriptional regulator of gene expression, intricately involved in various tumorigenic processes. However, the precise mechanisms governing m5C modifications during the onset and progression of colorectal cancer (CRC) remain poorly elucidated. In this study, it is determined that the m5C methyltransferase NSUN2 is markedly overexpressed and plays a pivotal oncogenic role in CRC. Mechanistically, NSUN2 and YBX1 have been identified as the "writer" and "reader" of ENO1, respectively, which leads to a metabolic reprogramming characterized by altered glucose metabolism and enhanced lactic acid production in an m5C-dependent manner. The accumulation of lactic acid produced by CRC cells subsequently triggers the transcriptional activation of NSUN2 via histone H3K18 lactylation (H3K18la). Additionally, this process induces lactylation of NSUN2 at the Lys356 residue (K356), a modification critical for the efficient binding of target RNAs. These findings unveil a compelling positive feedback loop involving the NSUN2/YBX1/m5C-ENO1 signaling axis. This loop establishes a connection between metabolic reprogramming and epigenetic modifications, highlighting a novel mechanism by which metabolic changes drive cancer progression. The study suggests that targeting this pathway with NSUN2 inhibitors, in conjunction with immunotherapy, may offer a promising therapeutic strategy for CRC, potentially improving treatment outcomes and offering new avenues for clinical intervention.
DOI: 10.1002/advs.202309840
02
Cancer Res. 2024.
Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous disease often associated with relapse after standard radiotherapies and cytotoxic chemotherapies. Combination therapies hold promise for addressing refractory metastatic TNBC. This study aimed to develop an antibody-drug conjugate with dual payloads (DualADC) as a chemo-immunotherapy for TNBC. It was found that overexpression of the immune checkpoint transmembrane protein CD276 (also known as B7-H3) is linked to angiogenesis, metastasis, and immune tolerance in over 60% of TNBC patients. In contrast to traditional antibody-drug conjugates (ADCs) that utilize a monoclonal antibody (mAb) to deliver a single payload, their DualADC is composed of a CD276 mAb, a highly potent drug (MMAF), and an immune booster TLR agonist (IMQ). Their DualADC, which integrates cancer proliferation inhibition, enhancement of tumoral cytokines, reactivation of immune cells, and modulation of the tumor microenvironment (TME), was shown to effectively eradicate TNBC cells in vivo. The underlying anti-cancer mechanisms were investigated using multiple research approaches, including H&E staining to assess tumor cell death, immunohistochemistry (IHC) with various antibodies to analyze tumoral immunity, Luminex assays to quantify tumoral cytokine secretion and evaluate cytokine storms, whole blood analysis, and single-cell RNA sequencing (scRNA-Seq) to examine immune cell infiltration, immune responses, and mitotic activities within the tumor microenvironment (TME). The study suggests that the developed DualADC could represent a promising targeted chemo-immunotherapy for TNBC.
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