NF-κB and STAT3 are key transcription factors involved in various physiological processes, including cancer development. Both are activated by different signaling mechanisms and regulate genes involved in cell survival, proliferation, and immune responses. They often collaborate, with their interactions playing a critical role in controlling the communication between malignant cells and the tumor microenvironment, particularly with inflammatory and immune cells. Cytokines produced in the tumor microenvironment can activate both factors, contributing to cancer progression. While STAT3 has oncogenic functions in malignant cells, it can also suppress tumor growth through anti-inflammatory effects in immune cells. NF-κB and STAT3 interact through physical binding, gene promoter cooperation, and regulatory feedback loops, which can be either synergistic or antagonistic. Despite these interactions, they cooperate to promote the development and progression of cancers such as colon, gastric, and liver cancers. Their interactions also offer therapeutic opportunities. NF-κB and STAT3 regulate genes involved in tumor growth, survival, angiogenesis, and immune responses. They control the expression of anti-apoptotic genes, cell cycle regulators, and cytokines that promote tumor growth. In immune cells, they influence inflammation and tumor promotion. The interplay between NF-κB and STAT3 in immune and cancer cells is crucial for tumor development, as seen in colitis-associated cancer (CAC). In CAC, NF-κB and STAT3 activation in immune cells and epithelial cells is essential for tumor progression. Targeting these pathways may provide new therapeutic strategies for cancer treatment. However, inhibitors of NF-κB or STAT3 must be carefully considered due to potential side effects, and their use should be combined with other therapies. Overall, the collaboration between NF-κB and STAT3 in cancer is complex and multifaceted, with significant implications for cancer therapy.NF-κB and STAT3 are key transcription factors involved in various physiological processes, including cancer development. Both are activated by different signaling mechanisms and regulate genes involved in cell survival, proliferation, and immune responses. They often collaborate, with their interactions playing a critical role in controlling the communication between malignant cells and the tumor microenvironment, particularly with inflammatory and immune cells. Cytokines produced in the tumor microenvironment can activate both factors, contributing to cancer progression. While STAT3 has oncogenic functions in malignant cells, it can also suppress tumor growth through anti-inflammatory effects in immune cells. NF-κB and STAT3 interact through physical binding, gene promoter cooperation, and regulatory feedback loops, which can be either synergistic or antagonistic. Despite these interactions, they cooperate to promote the development and progression of cancers such as colon, gastric, and liver cancers. Their interactions also offer therapeutic opportunities. NF-κB and STAT3 regulate genes involved in tumor growth, survival, angiogenesis, and immune responses. They control the expression of anti-apoptotic genes, cell cycle regulators, and cytokines that promote tumor growth. In immune cells, they influence inflammation and tumor promotion. The interplay between NF-κB and STAT3 in immune and cancer cells is crucial for tumor development, as seen in colitis-associated cancer (CAC). In CAC, NF-κB and STAT3 activation in immune cells and epithelial cells is essential for tumor progression. Targeting these pathways may provide new therapeutic strategies for cancer treatment. However, inhibitors of NF-κB or STAT3 must be carefully considered due to potential side effects, and their use should be combined with other therapies. Overall, the collaboration between NF-κB and STAT3 in cancer is complex and multifaceted, with significant implications for cancer therapy.