# The authors respond to feedback on Cancer Cell-Memory Macrophage Hybrid Theory for metastatic cancer cells

## TL;DR

The paper presents a new theory that metastatic cancer cells are hybrids of cancer cells and memory macrophages, explaining various puzzling cancer behaviors and offering new treatment strategies.

## Contribution

The novel contribution is the Cancer Cell-Memory Macrophage Hybrid Theory, which explains metastasis and cancer dormancy through hybrid cell properties.

## Key findings

- The hybrid cell model explains metastatic cancer dormancy and recurrence via stem-like self-renewal.
- The theory addresses clinical puzzles like microbial effects on cancer and immune responses to HPV vaccines.
- It proposes dampening hybrid macrophage-cancer cells and developing Coley’s toxin-like microbes as new anti-cancer strategies.

## Abstract

We have recently hypothesized that the hematogenous metastatic cancer cell of solid tumors is a hybrid between a primary cancer cell and a memory/trained macrophage (doi: 10.3389/fonc.2024.1412296). The hybrid cell respectively acquires mutator phenotype and overgrowth/hyperplasia property from the primary cancer cell and migratability/metastability from the memory/trained macrophage. We name this hypothesis Cancer Cell-Memory Macrophage Hybrid Theory. Since the publication of the article, a number of questions related to this Theory have been raised by colleagues in the oncology community, including intratumoral microbes and microbiomes/microbiotas, oncolytic viruses and bacteria, human papilloma virus vaccines, anti-cancer effects of γδ T-cells, and immune checkpoint inhibitors. The current article is prepared to address these issues. Additional to resolving questions like “Why metastatic cancer cells enter dormancy and can recur via stem-like self-renewal?”, the Cancer Cell-Memory Macrophage Hybrid Theory distinguishes itself from other carcinogenesis and metastasis hypotheses/theories by offering answers to many puzzling clinical features including metastasis of seemingly malignant parasitic cells within the human body, intracellular microbes (including viruses, bacteria, fungi, and parasites) within cancer cells, paradoxal effects (recurrence vs. regression) of microbes on cancer, contradictory immune effects of human papilloma virus vaccines between young and adult/senior females, and immune context-dependent effects (stimulatory and inhibitory) of T-lymphocytes on cancer cells. The Theory also predicts that quantitatively and functionally dampening innate macrophages that have hybridized with cancer cells (i.e., cancer cell-memory macrophage hybrids), should be explored as a fundamental anti-cancer strategy. The Theory further forecasts how to prepare an organotropic/tumoritropic Coley’s toxin-like anti-cancer microbe, which could potentially circumvent direct injection of microbial preparations into a tumor. A testable experiment that uses zebrafish larva models can potentially either validate or falsify the Theory.