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Microorganisms within the gut and other niches may contribute to carcinogenesis, as well as shaping cancer immunosurveillance and response to immunotherapy. Our understanding of the complex relationship between different host-intrinsic microorganisms, as well as the multifaceted mechanisms by which they influence health and disease, has grown tremendously—hastening development of novel therapeutic strategies that target the microbiota to improve treatment outcomes in cancer. Accordingly, the evaluation of a patient’s microbial composition and function and its subsequent targeted modulation represent key elements of future multidisciplinary and precision-medicine approaches. In this Review, we outline the current state of research toward harnessing the microbiome to better prevent and treat cancer. There exists tremendous opportunity to target microorganisms in the gut and other niches to help treat or even prevent cancer. This Review outlines how microbial targeting could become a pillar of personalized cancer care over the next 5 to 10 years.

Conventional chemotherapeutics have been developed into clinically useful agents based on their ability to preferentially kill malignant cells, generally owing to their elevated proliferation rate. Nonetheless, the clinical activity of various chemotherapies is now known to involve the stimulation of anticancer immunity either by initiating the release of immunostimulatory molecules from dying cancer cells or by mediating off-target effects on immune cell populations. Understanding the precise immunological mechanisms that underlie the efficacy of chemotherapy has the potential not only to enable the identification of superior biomarkers of response but also to accelerate the development of synergistic combination regimens that enhance the clinical effectiveness of immune checkpoint inhibitors (ICIs) relative to their effectiveness as monotherapies. Indeed, accumulating evidence supports the clinical value of combining appropriately dosed chemotherapies with ICIs. In this Review, we discuss preclinical and clinical data on the immunostimulatory effects of conventional chemotherapeutics in the context of ICI-based immunotherapy.The efficacy of chemotherapy in patients with cancer is now known to have an immunogenic component. Nonetheless, chemotherapy alone often fails to provide durable disease remission in most patients. The development of immune checkpoint inhibitors has created an opportunity to combine immunogenic chemotherapies with these agents in order to optimize patient outcomes. In this Review, the authors describe the mechanisms of synergy between chemotherapy and immune checkpoint inhibitors, summarize the available clinical data on these effects and highlight the most promising areas for future research.

Patients with kidney cancer who took probiotic supplements of Clostridium butyricum had improved response to immunotherapy, according to a randomized phase 1 study.

The fine line between human health and disease can be driven by the interplay between host and microbial factors. This “metagenome” regulates cancer initiation, progression, and response to therapies. Besides the capacity of distinct microbial species to modulate the pharmacodynamics of chemotherapeutic drugs, symbiosis between epithelial barriers and their microbial ecosystems has a major impact on the local and distant immune system, markedly influencing clinical outcome in cancer patients. Efficacy of cancer immunotherapy with immune checkpoint antibodies can be diminished with administration of antibiotics, and superior efficacy is observed with the presence of specific gut microbes. Future strategies of precision medicine will likely rely on novel diagnostic and therapeutic tools with which to identify and correct defects in the microbiome that compromise therapeutic efficacy.

Key Points Throughout the past century, conventional anticancer chemotherapeutics have been used based on their ability to selectively kill neoplastic cells while sparing their normal counterparts. More recently, targeted anticancer agents have been developed following the identification of cancer cell-specific molecular targets. The classical notion that cancer constitutes a cell-autonomous genetic disease has progressively been invalidated, along with the understanding that the tumour microenvironment (including stromal and immune components) is a crucial determinant for tumour progression and response to therapy. Local and systemic indicators of an ongoing response as well as biomarkers that predict the propensity of the immune system to engage in an anticancer immune response have been correlated with therapeutic outcome. Several conventional and targeted anticancer chemotherapeutics can induce tumour-specific immune responses, either by triggering immunogenic cancer cell death or by eliciting innate or cognate immune effector mechanisms. Conventional chemotherapeutics and targeted agents ameliorate the efficacy of several types of anticancer immunotherapy, including vaccination approaches and cytokine-mediated immunostimulation. Immunochemotherapy currently appears to be a promising strategy for the eradication of cancer. It can be anticipated that the elucidation of the intricate crosstalk among cancer, stromal cells and immune cells will provide additional targets for anticancer therapy. A crucial role of the immune system in cancer progression and response to therapy has recently emerged. Here, Galluzzi and colleagues discuss the immune parameters that may predict the therapeutic response of patients to chemotherapeutics, and review the mechanisms by which current antineoplastic agents activate the immune system against cancer. It has recently become clear that the tumour microenvironment, and in particular the immune system, has a crucial role in modulating tumour progression and response to therapy. Indicators of an ongoing immune response, such as the composition of the intratumoural immune infiltrate, as well as polymorphisms in genes encoding immune modulators, have been correlated with therapeutic outcome. Moreover, several anticancer agents — including classical chemotherapeutics and targeted compounds — stimulate tumour-specific immune responses either by inducing the immunogenic death of tumour cells or by engaging immune effector mechanisms. Here, we discuss the molecular and cellular circuitries whereby cytotoxic agents can activate the immune system against cancer, and their therapeutic implications.

There have been substantial advances in cancer diagnostics and therapies in the past decade. Besides chemotherapeutic agents and radiation therapy, approaches now include targeting cancer cell—intrinsic mediators linked to genetic aberrations in cancer cells, in addition to cancer cell—extrinsic pathways, especially those regulating vascular programming of solid tumors. More recently, immunotherapeutics have entered the clinic largely on the basis of the recognition that several immune cell subsets, when chronically activated, foster tumor development. Here, we discuss clinical and experimental studies delineating protumorigenic roles for immune cell subsets that are players in cancer-associated inflammation. Some of these cells can be targeted to reprogram their function, leading to resolution, or at least neutralization, of cancer-promoting chronic inflammation, thereby facilitating cancer rejection.

Key Points The evolution of cancer has been linked to shifts in the microbiome. It will be indispensable to identify individual strains and clones (rather than phyla and genera) that have optimal anticancer effects. For this, culturomics will be superior to deep-sequencing approaches. Therapeutic manipulation of the cancer-associated microbiome may be obtained by faecal microbiota transplantation, antibiotic treatment, prebiotics that favour the expansion of useful bacteria, dietary interventions or drugs that alter the composition of the gut flora. In preclinical models, defined strains of live microbial agents may be used to stimulate immunosurveillance against cancers, either alone or in combination with cancer therapeutics. Bacterial products that have potential antineoplastic or immunostimulatory properties include bacterial toxins, microbial ligands of pattern recognition receptors, as well as bacterial metabolites, including butyrate, polyamines and pyridoxine. Drugs that modify bacterial metabolism are being developed with the scope of inhibiting the production of carcinogenic products. The microbiota influences the development of cancer and the effect of cancer therapies. In this Review, the authors summarize the interactions between the microbiota, the immune system and tumours and how manipulation of the microbiota can be used therapeutically. The human gut microbiome modulates many host processes, including metabolism, inflammation, and immune and cellular responses. It is becoming increasingly apparent that the microbiome can also influence the development of cancer. In preclinical models, the host response to cancer treatment has been improved by modulating the gut microbiome; this is known to have an altered composition in many diseases, including cancer. In addition, cancer treatment with microbial agents or their products has the potential to shrink tumours. However, the microbiome could also negatively influence cancer prognosis through the production of potentially oncogenic toxins and metabolites by bacteria. Thus, future antineoplastic treatments could combine the modulation of the microbiome and its products with immunotherapeutics and more conventional approaches that directly target malignant cells.

Zitvogel and Kroemer focus on boosting the immunotherapy response by nutritional interventions. Immune checkpoint inhibitors (ICIs) targeting the interaction between programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) constitute the backbone of the oncological armamentarium. Nutritional interventions are now being considered as a possible strategy for improving the efficacy of immunotherapy. Indeed, three rather different types of dietary interventions are being considered at the clinical level for boosting immunotherapeutic responses: fasting regimens involving a reduction of caloric intake; ketogenic diets, which are low-carbohydrate, high-fat, sufficient-protein diets leading to an increase in ketone bodies; and the supplementation with polyphenol- rich extracts from an Amazonian berry, camu-camu.

There is currently much interest in defining how the microbiota shapes immune responses in the context of cancer. Various studies in both mice and humans have associated particular commensal species with better (or worse) outcomes in different cancer types and following treatment with cancer immunotherapies. However, the mechanisms involved remain ill-defined and even controversial. In this Viewpoint, Nature Reviews Immunology has invited six eminent scientists in the field to share their thoughts on the key questions and challenges for the field.In this Viewpoint, six leading experts consider the ways in which the microbiota can influence immune responses to cancer. Immunotherapies have been revolutionary in the treatment of cancer, but will we one day further increase their efficacy with microbiota-derived drugs?