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

Jiaxi Wu^1*Chuo Jiang²

• ¹Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences (CAS), Shanghai, China
• ²Shanghai University, Shanghai, China

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, and human papilloma virus vaccines, anti-cancer effects of γδ T-cells, immune checkpoint inhibitors. The current article is prepared to address these issues. Additional to resolve 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 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 these microbial preparations into a tumor. A testable experiment that uses zebrafish larva models can potentially either validate or falsify the Theory.