Current treatment protocols are not curative for some cancers, despite significant advancements in cancer research. To enhance the treatment of cancer, it is therefore crucial to investigate novel therapeutic targets and approaches. Metronomic chemotherapy (MCT) is novel and effective treatment approach for solid tumors and blood malignancies which entails the continuous administration of low-dose cytotoxic medications in contrast to conventional chemotherapy regimens. The main characteristics of MCT are: frequent, uninterrupted, dose-dense chemotherapy administration; use of a biologically optimized dose instead of MTD; low incidence of treatment-related side effects; inclination toward oral medications; and potential for delayed resistance development. MCT could induce tumor dormancy, suppress tumor angiogenesis, and strengthen the immune system’s defence against tumors. Celecoxib and methotrexate are the two main medications recommended for OMCT in numerous publications. Quality of life (QOL) and related side effects are a crucial factor that shifts the scales in favour of the OMCT. Immune checkpoint inhibitors (ICIs) have revolutionized the way many cancer types are treated. Boosting host anti-tumor immunity is the aim of immunotherapy. Combining immunotherapy with MCT can stimulate the production of tumor antigen-specific T lymphocytes in the host, which can enhance the anti-tumor effects in a synergistic manner and may offer a way to target cells that are resistant to therapy without causing unacceptable toxicity. This could lead to increased treatment adherence, better long-term results for cancers that are challenging to treat, and an improvement in the quality of life for patients.