Combination therapy is a key strategy in cancer treatment, combining two or more agents to target cancer pathways more effectively than single-agent therapy. This approach enhances efficacy by synergistically or additively targeting key pathways, reduces drug resistance, and provides therapeutic benefits such as reducing tumor growth, metastasis, and inducing apoptosis. However, developing new anti-cancer drugs is costly and time-consuming, prompting the exploration of repurposed drugs that are already FDA-approved for other conditions but may target cancer pathways. Combination therapy using FDA-approved drugs is more cost-effective and beneficial for medically underserved populations. Repurposed drugs, such as acetazolamide and rapalog, have shown promise in cancer treatment by targeting pathways like Nrf2-Keap1, HIF-1alpha, and carbonic anhydrase. The Nrf2-Keap1 pathway is crucial for antioxidant response and tumorigenesis. Nrf2 activation helps cancer cells cope with oxidative stress, and its regulation involves both Keap1-dependent and independent mechanisms. Agents like curcumin, resveratrol, and sulforaphane can upregulate Nrf2, enhancing antioxidant effects and reducing cancer cell survival. Similarly, hypoxia and the carbonic anhydrase pathway are critical in cancer progression, with carbonic anhydrase inhibitors (CAIs) showing potential in targeting cancer cells by inhibiting CAIX, a marker of poor prognosis. HDAC inhibitors, such as valproic acid and romidepsin, have shown efficacy in cancer treatment by modulating epigenetic factors and enhancing chemotherapy responses. Combination therapies involving HDAC inhibitors and other agents, like AZ and MS-275, have demonstrated improved outcomes in preclinical and clinical studies. Autocrine growth factors, such as 5-HT, play a significant role in cancer proliferation and survival. Targeting these factors through combination therapies, including repurposed drugs like AZ and SFN, has shown promise in reducing tumor growth and improving therapeutic outcomes. Overall, combination therapies targeting multiple pathways offer a more effective and efficient approach to cancer treatment, with ongoing research aiming to optimize these strategies for clinical application.Combination therapy is a key strategy in cancer treatment, combining two or more agents to target cancer pathways more effectively than single-agent therapy. This approach enhances efficacy by synergistically or additively targeting key pathways, reduces drug resistance, and provides therapeutic benefits such as reducing tumor growth, metastasis, and inducing apoptosis. However, developing new anti-cancer drugs is costly and time-consuming, prompting the exploration of repurposed drugs that are already FDA-approved for other conditions but may target cancer pathways. Combination therapy using FDA-approved drugs is more cost-effective and beneficial for medically underserved populations. Repurposed drugs, such as acetazolamide and rapalog, have shown promise in cancer treatment by targeting pathways like Nrf2-Keap1, HIF-1alpha, and carbonic anhydrase. The Nrf2-Keap1 pathway is crucial for antioxidant response and tumorigenesis. Nrf2 activation helps cancer cells cope with oxidative stress, and its regulation involves both Keap1-dependent and independent mechanisms. Agents like curcumin, resveratrol, and sulforaphane can upregulate Nrf2, enhancing antioxidant effects and reducing cancer cell survival. Similarly, hypoxia and the carbonic anhydrase pathway are critical in cancer progression, with carbonic anhydrase inhibitors (CAIs) showing potential in targeting cancer cells by inhibiting CAIX, a marker of poor prognosis. HDAC inhibitors, such as valproic acid and romidepsin, have shown efficacy in cancer treatment by modulating epigenetic factors and enhancing chemotherapy responses. Combination therapies involving HDAC inhibitors and other agents, like AZ and MS-275, have demonstrated improved outcomes in preclinical and clinical studies. Autocrine growth factors, such as 5-HT, play a significant role in cancer proliferation and survival. Targeting these factors through combination therapies, including repurposed drugs like AZ and SFN, has shown promise in reducing tumor growth and improving therapeutic outcomes. Overall, combination therapies targeting multiple pathways offer a more effective and efficient approach to cancer treatment, with ongoing research aiming to optimize these strategies for clinical application.