Microorganisms, including bacteria, viruses, fungi, and other eukaryotes, play critical roles in human health. An altered microbiome can be associated with complex diseases. Intratumoral microbial components are found in multiple tumor tissues and are closely correlated with cancer initiation and development and therapy efficacy. The intratumoral microbiota may contribute to promotion of the initiation and progression of cancers by DNA mutations, activating carcinogenic pathways, promoting chronic inflammation, complement system, and initiating metastasis. Moreover, the intratumoral microbiota may not only enhance antitumor immunity via mechanisms including STING signaling activation, T and NK cell activation, TLS production, and intratumoral microbiota-derived antigen presenting, but also decrease antitumor immune responses and promote cancer progression through pathways including upregulation of ROS, promoting an anti-inflammatory environment, T cell inactivation, and immunosuppression. The effect of intratumoral microbiota on antitumor immunity is dependent on microbiota composition, crosstalk between microbiota and the cancer, and status of cancers. The intratumoral microbiota may regulate cancer cell physiology and the immune response by different signaling pathways, including ROS, β-catenin, TLR, ERK, NF-κB, and STING, among others. These viewpoints may help identify the microbiota as diagnosis or prognosis evaluation of cancers, and as new therapeutic strategy and potential therapeutic targets for cancer therapy.
Humans contain a large number of microorganisms, which play critical roles in human health.1The human commensal microbiome includes bacteria, viruses, fungi, and other eukaryotic species,2 which can inhabit many sites in the human body, including the mouth, gastrointestinal tract, reproductive system organs, and skin.3,4
Many studies of the human microbiome indicate that the microbiota differs between healthy and diseased individuals. In particular, the microbiota has a close relationship with cancer; it affects carcinogenesis in the human body.5 Oncoviruses induce tumorigenesis by integrating oncogenes into the human host genome. Interestingly, different intratumoral microbial components, which are significantly correlated with cancer initiation and development, have been found and evaluated in several kinds of tumor tissues. Garrett et al.6 reported three ways in which the microbiota may lead to tumor progression and development: (1) changing the balance of cell proliferation and apoptosis, (2) reprogramming the immune system and responses, and (3) affecting the metabolism of host-secreted factors, foods, and drugs.
Many studies have shown that the gut microbiota is essential for the regulation of host immune responses. However, the intratumoral microbiota may also play a key role in shaping the local immune responses of the tumor microenvironment, which further affects tumor progression. The intratumoral microbiota play different roles in antitumor immunity: by either enhancing or decreasing antitumor immune responses and inducing different immunotherapy efficacies and outcomes.7,8
In this review, we describe the intratumoral microbiota in a comprehensive way, including the history and milestones, the origin, the diversity of intratumoral microbiota, the relationship between intratumoral and gut microbiota, the effect of the intratumoral microbiota on cancer development, antitumor immunity and therapeutic efficacy, and the usage of intratumoral microbiota for therapy, diagnosis and prognosis of cancers. These findings may help identify new therapeutic strategies and targets of intratumoral microbiota for cancer therapy.
History and milestones of intratumoral microbiota
The key research milestones of intratumoral microbiota were retrospectively summarized (Fig. 1). The history of microbes in tumors can be traced back to as early as 1550 BC, when the Egyptian physician Imhotep (2600 BC) treated tumors by incising swellings and then causing infection.9,10 In the 13th century, Peregrine Laziosi (1265–1345) had a huge growth on his tibia and developed a severe infection after amputation, but the cancer never returned, and centuries later he was named the patron saint of cancer patients.11 Subsequent reports of spontaneous tumor regression following infection followed, and by the 18th and 19th centuries, this crude cancer immunotherapy was widely recognized and accepted.12 It was not until the late 1800s that William Coley successfully treated sarcoma patients with a vaccine made of two inactivated bacteria (Streptococcus pyogenes and Serratia marcescens) by direct injection into the tumor site, which was promoted as the first intentional demonstration of immunotherapy and promoted.10,13,14 In the 1900s, Thomas Glover and Virginia Livingston-Wheeler claimed that bacteria could be grown from tumors and suggested a common bacterial origin for cancer, but ultimately proved their theories incorrect.14,15,16 In 1911, Peyton Rous discovered that the breast tumor filtrate of chickens can lead to a transmissible sarcoma, which may be caused by a minute parasitic organism, triggering the theory of the origin of cancer viruses.17 In the following decades, people have gradually discovered viruses that can induce carcinogenesis, such as the Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus, human papilloma virus, human T-cell lymphotropic virus, hepatitis B virus (HBV), hepatitis C virus (HCV), and Merkel cell polyomavirus (MCPyV). In 1983, Marshall and Warren cultured Helicobacter pylori and demonstrated its role in peptic ulcers,18,19 and subsequent studies proved that this bacterium can cause stomach cancer, which sparked a wave of research on how bacteria can cause cancer. Since the 21st century, with the development of sequencing technology, more and more articles have reported the existence of microbiota in tumors and revealed their importance in the tumor microenvironment and regulation of treatment outcomes.3,20,21,22,23,24,25,26,27,28 The widespread use of the Next Generation Sequencing has further advanced the study of intratumoral microbiota. In 2020, two large-scale studies on the microbiota in multiple tumors were reported. Poore et al. analyzed the diverse intratumoral microbiota in more than 30 cancers and proposed a new diagnostic tool based on microbiota for cancer.29 Shortly thereafter, Ravid Straussman’s team conducted the first comprehensive analysis of seven tumor microbiomes, which providing the intratumoral spatial distribution of these microbiota and imaging evidence of intracellular localization.8 In 2022, the team again revealed the distribution of fungi in 35 cancers, their localization in cells and synergistic effects with bacteria.30 Coincidentally, at the same time, Dohlman et al. analyzed The Cancer Genome Atlas data to discover disease-related fungi in cancers of the gastrointestinal tract, lungs, breast, head and neck, and studied the role of fungal DNA in diagnosis and prognosis.31
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