Chemokine-derived oncolytic peptide induces immunogenic cancer cell death and significantly suppresses tumor growth.

Chemokinostatin-1 (CKS1) is a 24-mer peptide originally discovered as an anti-angiogenic peptide derived from the CXCL1 chemokine. Here, we demonstrate that CKS1 acts not only as an anti-angiogenic peptide but also as an oncolytic peptide due to its structural and physical properties. CKS1 induced both necrotic and apoptotic cell death specifically in cancer cells while showing minimal toxicity in non-cancerous cells. Mechanistically, CKS1 disrupted the cell membrane of cancer cells quickly after treatment and activated the apoptotic pathway at later time points. Furthermore, immunogenic molecules were released from CKS1-treated cells, indicating that CKS1 induces immunogenic cell death. CKS1 effectively suppressed tumor growth in vivo. Collectively, these data demonstrate that CKS1 functions as an oncolytic peptide and has a therapeutic potential to treat cancer.

Chemokine-derived oncolytic peptide induces immunogenic cancer cell death and significantly suppresses tumor growth.

Chemokinostatin-1 (CKS1) is a 24-mer peptide originally discovered as an anti-angiogenic peptide derived from the CXCL1 chemokine. Here, we demonstrate that CKS1 acts not only as an anti-angiogenic peptide but also as an oncolytic peptide due to its structural and physical properties. CKS1 induced both necrotic and apoptotic cell death specifically in cancer cells while showing minimal toxicity in non-cancerous cells. Mechanistically, CKS1 disrupted the cell membrane of cancer cells quickly after treatment and activated the apoptotic pathway at later time points. Furthermore, immunogenic molecules were released from CKS1 treated cells, indicating that CKS1 induces immunogenic cell death. CKS1 effectively suppressed tumor growth in vivo. Collectively, these data demonstrate that CKS1 is a unique peptide that functions both as an anti-angiogenic peptide and as an oncolytic peptide and has a therapeutic potential to treat cancer.

The tumor microenvironment and triple-negative breast cancer aggressiveness: shedding light on mechanisms and targeting.

INTRODUCTION: In contrast to other breast cancer subtypes, there are currently limited options of targeted therapies for triple-negative breast cancer (TNBC). Immense research has demonstrated that not only cancer cells but also stromal cells and immune cells in the tumor microenvironment (TME) play significant roles in the progression of TNBC. It is thus critical to understand the components of the TME of TNBC and the interactions between the various cell populations. AREAS COVERED: The components of the TME of TNBC identified by single-cell technologies are reviewed. Furthermore, the molecular interactions between the cells and the potential therapeutic targets contributing to the progression of TNBC are discussed. EXPERT OPINION: Single-cell omics studies have contributed to the classification of cells in the TME and the identification of important cell types involved in the progression and the treatment of the tumor. The interactions between cancer cells and stromal cells/immune cells in the TME have led to the discovery of potential therapeutic targets. Experimental data with spatial and temporal resolution will further boost the understanding of the TME of TNBC.

ASK1 suppresses NK cell-mediated intravascular tumor cell clearance in lung metastasis.

Tumor metastasis is the leading cause of death worldwide and involves an extremely complex process composed of multiple steps. Our previous study demonstrated that apoptosis signal-regulating kinase 1 (ASK1) deficiency in mice attenuates tumor metastasis in an experimental lung metastasis model. However, the steps of tumor metastasis regulated by ASK1 remain unclear. Here, we showed that ASK1 deficiency in mice promotes natural killer (NK) cell-mediated intravascular tumor cell clearance in the initial hours of metastasis. In response to tumor inoculation, ASK1 deficiency upregulated immune response-related genes, including interferon-gamma (IFNγ). We also revealed that NK cells are required for these anti-metastatic phenotypes. ASK1 deficiency augmented cytokine production chemoattractive to NK cells possibly through induction of the ligand for NKG2D, a key activating receptor of NK cells, leading to further recruitment of NK cells into the lung. These results indicate that ASK1 negatively regulates NK cell-dependent anti-tumor immunity and that ASK1-targeted therapy can provide a new tool for cancer immunotherapy to overcome tumor metastasis.

Peptides that immunoactivate the tumor microenvironment.

Cancer immunotherapy has achieved positive clinical outcomes and is revolutionizing cancer treatment. However, cancer immunotherapy has thus far failed to improve outcomes for most "cold tumors", which are characterized by low infiltration of immune cells and immunosuppressive tumor microenvironment. Enhancing the responsiveness of cold tumors to cancer immunotherapy by stimulating the components of the tumor microenvironment is a strategy pursued in the last decade. Currently, most of the agents used to modify the tumor microenvironment are small molecules or antibodies. Small molecules exhibit low affinity and specificity towards the target and antibodies have shortcomings such as poor tissue penetration and high production cost. Peptides may overcome these drawbacks and therefore are promising materials for immunomodulating agents. Here we systematically summarize the currently developed immunoactivating peptides and discuss the potential of peptide therapeutics in cancer immunology.