IL-1α is a dual function cytokine that affects inflammatory and immune responses and plays a pivotal role in cancer. The effects of intracellular IL-1α on the development of triple negative breast cancer (TNBC) in mice were assessed using the CRISPR/Cas9 system to suppress IL-1α expression in 4T1 breast cancer cells. Knockout of IL-1α in 4T1 cells modified expression of multiple genes, including downregulation of cytokines and chemokines involved in the recruitment of tumor-associated pro-inflammatory cells. Orthotopical injection of IL-1α knockout (KO) 4T1 cells into BALB/c mice led to a significant decrease in local tumor growth and lung metastases, compared to injection of wild-type 4T1 (4T1/WT) cells. Neutrophils and myeloid-derived suppressor cells were abundant in tumors developing after injection of 4T1/WT cells, whereas more antigen-presenting cells were observed in the tumor microenvironment after injection of IL-1α KO 4T1 cells. This switch correlated with increased infiltration of CD3⁺CD8⁺ and NKp46⁺cells. Engraftment of IL-1α knockout 4T1 cells into immunodeficient NOD.SCID mice resulted in more rapid tumor growth, with increased lung metastasis in comparison to engraftment of 4T1/WT cells. Our results suggest that tumor-associated IL-1α is involved in TNBC progression in mice by modulating the interplay between immunosuppressive pro-inflammatory cells vs. antigen-presenting and cytotoxic cells.

(1) Background: Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. The tumor microenvironment (TME) is a key driver of disease progression, shaping both pro- and anti-tumor immune responses. Interleukin-1β (IL-1β) is a pleiotropic pro-inflammatory cytokine that participates in both homeostatic and pathological conditions. It has been shown to be upregulated in many tumors, including CRC, where it promotes angiogenesis, immunosuppression, and resistance to chemotherapy. (2) Objective: Elucidate the correlation between TME IL-1β and colon microbiotic changes during CRC progression and approach inhibition of IL-1β as a therapeutic strategy in combination with chemotherapy. (3) Design: Using an orthotopic mouse model of CRC, we compared tumor growth, metastatic spread, immune infiltration and microbiome composition in control and IL-1β knockout mice. In addition, we studied the effects of IL-1β neutralization alone or in combination with FOLFOX chemotherapy on CRC prognosis. (4) Results: IL-1β promoted CRC progression by enhancing pro-inflammatory signalling, recruiting immunosuppressive myeloid cells, and driving microbiome dysbiosis. In contrast, IL-1β deficiency increased antigen-presenting myeloid cells and CD⁸⁺ T-cell infiltration, leading to delayed tumor growth and reduced metastasis. FOLFOX chemotherapy alone exacerbated systemic and local inflammation, facilitating liver metastasis. Strikingly, the addition of IL-1β blockade abrogated FOLFOX-induced inflammation, enhanced anti-tumor immunity, and prevented metastatic spread. (5) Conclusions: IL-1β from the TME links microbiome dysbiosis, tumor-promoting inflammation and poor chemotherapy outcomes in CRC. Combining IL-1β inhibition with standard FOLFOX chemotherapy represents a promising therapeutic approach to improve prognosis in CRC patients.