Over the last decade, mounting evidence has revealed the key roles of gut microbiota in modulating the efficacy and toxicity of anticancer drugs, via mechanisms such as immunomodulation and microbial enzymatic degradation. As such, human microbiota presents as an exciting prospect for developing biomarkers for predicting treatment outcomes and interventional approaches for improving therapeutic effects. In this review, we analyze the current knowledge of the interplays among gut microorganisms, host responses and anticancer therapies (including cytotoxic chemotherapy and targeted therapy), with an emphasis on the immunomodulation function of microbiota which facilitates the efficacy of immune checkpoint inhibitors. Moreover, we propose several microbiota-modulating strategies including fecal microbiota transplantation and probiotics, which can be pursued to optimize the use and development of anticancer treatments. We anticipate that future clinical and preclinical studies will highlight the significance of human microbiome as a promising target towards precision medicine in cancer therapies.
Cancer is a major public health burden and a leading cause of human death worldwide. Globally, more than 19.3 million cancer cases are newly diagnosed per annum and over 9.9 million individuals die as a consequence. Remarkable advances have been made in tackling cancer in recent years, including early detection, diagnosis, and cancer treatment. A stepwise increase in numbers of anticancer drug approval was recorded from the year 2009 (8 approvals) to the year 2020 (57 approvals). These newly approved drugs have largely enriched the therapeutic options, and enhanced the survival and quality of life of cancer patients. Clinical use of anticancer drugs varies based on tumor location, age, disease stage, metastatic state, genetic heterogeneity, etc.
Taking colorectal cancer as an example, in patients with high-risk stage II and III colorectal cancer, defined as those with poor prognostic features, adjuvant systemic chemotherapy provides an overall survival benefit. First-line regimens are typically based on various combinations of cytotoxic drugs oxaliplatin, 5-fluorouracil (5-FU), capecitabine, and leucovorin. However, prolonged administration, lack of specificity and disparate cytotoxic adverse effects are major limitations in their clinical applications.Between 2004 and 2006, three novel monoclonal antibodies (bevacizumab, cetuximab, and panitumumab) as targeted therapies came into use for treating metastatic colorectal cancer, whereas they are only indicated to certain genetic types, and mainly used in combinations with cytotoxic chemotherapies.
Since 2017, three immune checkpoint inhibitor (ICI) drugs (e.g., pembrolizumab, nivolumab, and ipilimumab) have been clinically utilized for treating specific colorectal cancer subtypes, namely mismatch-repair-deficient (dMMR) microsatellite instability-high (MSI-H) subtypes. However, this type only comprises approximately 15% of all colorectal cancer patients, demonstrating that the majority of the patients cannot benefit from ICI therapies. For the reasons above, our current armory of effective medications against cancer cells is still limited, therefore, both new agents and predictive biomarkers for selecting beneficial therapies are urgently needed.
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