Non-small cell lung cancer (NSCLC) is one of the major cancer-related causes of morbidity and mortality worldwide. Despite the progress in lung cancer treatment, there is still an urgent need to discover novel therapeutic agents for NSCLC. Natural products represent a rich source of bioactive compounds. Through a natural compound library screening assay, we found that a group of anti-insect drugs had significant inhibitory effect on the proliferation of NSCLC cells. Among the anti-insect drugs, two derivatives of artemisinin, i.e., artesunate (ART) and dihydroartemisinin (DHA), a group of well-known anti-malarial drugs, have been shown to possess selective anti-cancer properties. Mechanistically, we found that ART and DHA induced apoptosis of A549 cells as evidenced by decreased protein level of VDAC and increased caspase 3 cleavage. Furthermore, cystine/glutamate transporter (xCT), a core negative regulator of ferroptosis, was downregulated by ART and DHA. The mRNA level of transferrin receptor (TFRC), a positive regulator of ferroptosis, was upregulated by ART and DHA. ART/DHA-induced apoptosis and ferroptosis in NSCLC cells were partly reversed by N-Acetyl-L-cysteine (NAC), a ROS scavenger, and ferrostatin-1, a ferroptosis inhibitor, respectively. These results suggest that artemisinin derivatives have anti-NSCLC activity through induction of ROS-dependent apoptosis/ferroptosis. Our findings provide the experimental basis for the potential application of artemisinin derivatives as a class of novel therapeutic drugs for NSCLC.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, which is characterized by the absence of estrogen receptor (ER) and progesterone receptor (PR) expression and the absence of human epidermal growth factor receptor 2 (HER2) expression/amplification. Conventional chemotherapy is the mainstay of systemic treatment for TNBC. However, lack of molecular targeted therapies and poor prognosis of TNBC patients have prompted a great effort to discover effective targets for improving the clinical outcomes. For now, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi’s) and immune checkpoint inhibitors have been approved for the treatment of TNBC. Moreover, agents that target signal transduction, angiogenesis, epigenetic modifications, and cell cycle are under active preclinical or clinical investigations. In this review, we highlight the current major developments in targeted therapies of TNBC, with some descriptions about their (dis)advantages and future perspectives.

Triple-negative breast cancer (TNBC) is characterized by the lack of clinically significant levels of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Owing to the aggressive nature and the emergence of resistance to chemotherapeutic drugs, patients with TNBC have a worse prognosis than other subtypes of breast cancer. Currently, immunotherapy using checkpoint blockade has been shown to produce unprecedented rates of long-lasting responses in patients with a variety of cancers. Although breast tumors, in general, are not highly immunogenic, TNBC has a higher level of lymphocyte infiltration, suggesting that TNBC patients may be more responsive to immunotherapy. The identification/characterization of immune checkpoint molecules, i.e., programmed cell death protein 1 (PD1), programmed cell death ligand 1 (PDL1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA4), represents a major advancement in the field of cancer immunotherapy. These molecules function to suppress signals downstream of T cell receptor (TCR) activation, leading to elimination of cytotoxic T lymphocytes (CTLs) and suppression of anti-tumor immunity. For TNBC, which has not seen substantial advances in clinical management for decades, immune checkpoint inhibition offers the opportunity of durable response and potential long-term benefit. In clinical investigations, immune checkpoint inhibition has yielded promising results in patients with early-stage as well as advanced TNBC. This review summarizes the recent development of immune checkpoint inhibition in TNBC, focusing on humanized antibodies targeting the PD1/PDL1 and the CTLA4 pathways.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Although immunotherapy is effective for some patients, most find it difficult to benefit from it. This study aims to explore the impact of specific immune pathways and their regulated molecular mechanisms in TNBC. The gene expression data of breast cancer patients were obtained from the TCGA and METABRIC databases. Gene set variation analysis (GSVA) revealed specific upregulation or abnormal expression of immunodeficiency pathways in TNBC patients. Multi-omics data showed significant differential expression of Primary Immunodeficiency Genes (PIDGs) in TNBC patients, who are prone to genomic-level variations. Consensus clustering was used in two datasets to classify patients into two distinct molecular subtypes based on PIDGs expression patterns, with each displaying different biological features and immune landscapes. To further explore the prognostic characteristics of PIDGs-regulated molecules, we constructed a four-gene prognostic PIDG score model and a nomogram using least absolute shrinkage and selection operator (LASSO) regression analysis in combination with clinicopathological parameters. The PIDG score was closely associated with the immune therapy and drug sensitivity of TNBC patients, providing potential guidance for clinical treatment. Particularly noteworthy is the close association of this scoring with RNA modifications; patients with different scores also exhibited different mutation landscapes. This study offers new insights for the clinical treatment of TNBC and for identifying novel prognostic markers and therapeutic targets in TNBC.

Lysine succinylation is an emerging post-translational modification of proteins. It involves the addition of the succinyl group to lysine residues of target proteins through both enzymatic and non-enzymatic pathways. This modification can alter the structure of the target protein, which, in turn, impacts protein activity and function and is involved in a wide range of diseases. In the field of cancer biology, lysine succinylation has been shown to exert a substantial influence on metabolic reprogramming of tumor cells, regulation of gene expression, and activation of oncogenic signaling pathways. Furthermore, lysine succinylation modulates the activity of immune cells, thereby affecting the immune evasion of tumor cells. Notably, researchers are currently developing inhibitors and activators of lysine succinylation which can inhibit tumor cell proliferation, migration, and metastasis, with potential usefulness in future clinical practice. This article provides an overview of the biological functions of lysine succinylation in cancer and its potential applications in cancer treatment, offering a novel perspective for future cancer management.