Interplay between hypoxia and inflammation in cancer progression, therapy resistance, and natural cancer resistance

Abstract

The microenvironment of solid tumors is characterized by dynamic availability of oxygen and persistent, complex inflammatory signaling. Accumulating evidence suggests that hypoxia and inflammation actively influence tumor progression and therapeutic response. In physiological conditions, hypoxic and inflammatory responses function as evolutionarily conserved protective mechanisms. Acute hypoxia promotes temporary metabolic adaptation to preserve tissue viability, while acute inflammation facilitates clearance of damaged or abnormal cells and restores homeostasis. In tumors, by contrast, hypoxia and inflammation become chronic and unresolved. Persistent activation of these protective signals gradually renders the microenvironment permissive to the sustained adaptation of abnormal cells rather than eliminating them. This transition from clearance to tolerance reshapes cellular metabolism, immune cell behavior, and tissue organization within the tumor microenvironment. As a result, tumor cells increasingly adapt to metabolic stress and evade effective immune surveillance, contributing to malignancy and therapy resistance. Interestingly, some subterranean species, including the naked mole rat and blind mole rat, show natural cancer resistance. They either evolved adaptations counteracting inflammation, or take the immune response to their advantage to prevent cancer. These anti-cancer mechanisms are a result of adaptation to their hypoxic subterranean habitats. In this review, we examine the fundamental features of hypoxia and inflammation in tumors, explore their functional interplay, and discuss how these mechanisms are evaded or harnessed by cancer resistant subterranean mammals. We further propose a simple clearance to resistance framework that links acute protective stress responses, chronic tumor-promoting adaptation, and naturally evolved cancer resistance.