Fusobacterium nucleatum: a novel regulator of antitumor immune checkpoint blockade therapy in colorectal cancer.

Neoadjuvant immune checkpoint blockade (ICB) has achieved significant success in treating various cancers, leading to improved therapeutic responses and survival rates among patients. However, in colorectal cancer (CRC), ICB has yielded poor results in tumors that are mismatch repair proficient, microsatellite-stable, or have low levels of microsatellite instability (MSI-L), which account for up to 95% of CRC cases. The underlying mechanisms behind the lack of immune response in MSI-negative CRC to immune checkpoint inhibitors remain an open conundrum. Consequently, there is an urgent need to explore the intrinsic mechanisms and related biomarkers to enhance the intratumoral immune response and render the tumor "immune-reactive". Intestinal microbes, such as the oral microbiome member Fusobacterium nucleatum (F. nucleatum), have recently been thought to play a crucial role in regulating effective immunotherapeutic responses. Herein, we advocate the idea that a complex interplay involving F. nucleatum, the local immune system, and the tumor microenvironment (TME) significantly influences ICB responses. Several mechanisms have been proposed, including the regulation of immune cell proliferation, inhibition of T lymphocyte, natural killer (NK) cell function, and invariant natural killer T (iNKT) cell function, as well as modification of the TME. This review aims to summarize the latest potential roles and mechanisms of F. nucleatum in antitumor immunotherapies for CRC. Additionally, it discusses the clinical application value of F. nucleatum as a biomarker for CRC and explores novel strategies, such as nano-delivery systems, for modulating F. nucleatum to enhance the efficacy of ICB therapy.

Inhibited Expression of NLRP12 Promotes the Development of Triple-Negative Breast Cancer by Activating the NF-κB Pathway.

NLRP12 can affect the progression of different diseases, including hepatocellular carcinoma. However, no report on triple-negative breast cancer (TNBC) has been found. Thus, this study aimed to explore the role of NLRP12 in TNBC. In our study, immunohistochemistry, real-time quantitative PCR (qPCR), and Western blot assays were used to evaluate NLRP12 expression in TNBC tissues and cells. Then, NLRP12 lentivirus was constructed and infected into MDA-MB-231 and MDA-MB-157 cells with or without PTD-p65-P1 treatment. Next, cells were collected for cell function detection using the following procedures: colony formation assay for proliferation, Transwell for migration and invasion, and Western blot for NF-κB and MAPK pathway-associated proteins. Finally, a xenograft mouse model was applied; the tumor volume and weight were determined, and NLRP12, p-IκBb-α, and p-IκBb-α expressions were evaluated using qPCR and Western blot. Results indicated that NLRP12 was lowly expressed in TNBC tissues and cells. The inhibition of NLRP12 could induce the proliferation, migration, and invasion of TNBC cells, which also could be reversed by inhibiting the NF-κB pathway (PTD-p65-P1). Moreover, silencing of NLRP12 could upregulate p-IκBb-α, while IκBb-α, p-ERK, ERK, p-p38, p38, p-JNK, and JNK expressions remained unchanged, thereby indicating that only the NF-κB pathway could be activated by NLRP12 silencing. Furthermore, the xenograft mouse model confirmed the abovementioned findings. Therefore, the low expression of NLRP12 promoted the proliferation, migration, and invasion in TNBC cells by activating the NF-κB pathway. This study might provide insights into TNBC therapy.

Mechanism of inflammasomes in cancer and targeted therapies.

Inflammasomes, composed of the nucleotide-binding oligomerization domain(NOD)-like receptors (NLRs), are immune-functional protein multimers that are closely linked to the host defense mechanism. When NLRs sense pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), they assemble into inflammasomes. Inflammasomes can activate various inflammatory signaling pathways, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, and produce a large number of proinflammatory cytokines, which are closely associated with multiple cancers. They can also accelerate the occurrence and development of cancer by providing suitable tumor microenvironments, promoting tumor cell proliferation, and inhibiting tumor cell apoptosis. Therefore, the exploitation of novel targeted drugs against various inflammasomes and proinflammatory cytokines is a new idea for the treatment of cancer. In recent years, more than 50 natural extracts and synthetic small molecule targeted drugs have been reported to be in the research stage or have been applied to the clinic. Herein, we will overview the mechanisms of inflammasomes in common cancers and discuss the therapeutic prospects of natural extracts and synthetic targeted agents.