# Intratumoral Microbiome: Impact on Cancer Progression and Cellular Immunotherapy

## TL;DR

This review explores how microbes inside tumors affect cancer growth and how immunotherapies like CAR-T cells work, highlighting the microbiome's role in shaping immune responses.

## Contribution

The paper reviews novel insights into how the intratumoral microbiome influences cancer progression and immunotherapy efficacy through immune modulation.

## Key findings

- The intratumoral microbiome influences carcinogenesis via DNA damage and oncogenic signaling pathways.
- Microbial interactions with immune cells can either suppress or enhance anti-tumor immune responses.
- The microbiome's composition is a key factor in determining immunotherapy outcomes.

## Abstract

Cellular immunotherapy is a growing field that has shown significant success in treating oncological diseases, utilizing living immune cells such as CAR-T cells and NK cells. However, challenges remain, particularly low efficacy in solid tumors and immunosuppression within the tumor microenvironment. Recent research supports the long-standing hypothesis that organs traditionally viewed as sterile, including tumor tissues, harbor diverse microbial communities, referred to as the intratumoral microbiome. This microbiome is recognized as an important element in cancer development and progression, exhibiting both stimulatory and inhibitory effects. The intratumoral microbiota strongly influences immune cell activity and regulates local and systemic immune responses. The aim of this review is to summarize data on the role of the intratumoral microbiome, with a primary focus on its bacterial component, in the development and progression of cancer, as well as the interaction of microorganisms in tumor tissue with immune cells, especially in the context of cellular immunotherapy.

The intratumoral microbiota, comprising bacteria, fungi, and viruses within the tumor microenvironment, actively influences carcinogenesis. Key mechanisms include the induction of host DNA damage, modulation of critical oncogenic signaling pathways such as WNT-β-catenin, NF-κB, and PI3K, and the orchestration of inflammatory processes. The microbiome’s interaction with the host immune system is complex and bidirectional. On one hand, specific microbes can foster a pro-tumorigenic niche by suppressing the activity of cytotoxic T cells and natural killer (NK) cells or by promoting the accumulation of immunosuppressive cell types like tumor-associated macrophages (TAMs). On the other hand, microbial components can serve as neoantigens for T cell recognition or produce metabolites that reprogram the immune landscape to enhance anti-tumor responses. The composition of this microbiome is emerging as a crucial factor influencing the outcomes of immunotherapies. Prospective investigations in cancer immunotherapy ought to prioritize mechanistic inquiry employing integrative multi-omics methodologies. The execution of meticulously designed clinical trials for the validation of microbial biomarkers, and the systematic, evidence-based development of microbiome-targeted therapeutic interventions aimed at enhancing antitumor immune responses.