Energy stress and adaptation strategy of tumor cells in different microenvironments: from primary tumors to distant metastases

Abstract

Since the Warburg effect was first described in the 1920s, tumor energy metabolism has been a central focus of cancer research, emerging as a potential therapeutic target. The tumor microenvironment—including blood vessels, immune cells, stromal components, and other cell types—profoundly influences tumor cell metabolism. Variations in energy supply, oxygen availability, nutrient composition, and the accumulation of metabolic waste across different microenvironments challenge tumor cell survival and progression. In response, tumor cells adapt through flexible regulation and reprogramming of metabolic pathways. Although recent studies have explored metabolic adaptation mechanisms in various tumor microenvironments, the full spectrum from primary tumors to distant metastases remains unexplored. This review summarizes energy stress and adaptation maneuvers in tumor cells across different stages of tumor progression and offers a new perspective for comprehensive research to explore therapeutic strategies targeting tumor metabolism.

1. Introduction

When normal cells in human tissues acquire mutations that lead to uncontrolled proliferation, tumorigenesis initiates [1]. At the stage of carcinoma in situ, tumor cells are confined to their site of origin without breaching the basement membrane or exhibiting invasion or distant metastasis. However, cancer cells are not restricted to the primary site; they possess a certain degree of invasive potential [2]. When carcinoma in situ cells undergo epithelial-mesenchymal transition (EMT), they gradually acquire invasiveness, thereby penetrating the basement membrane and entering surrounding tissues. They can then disseminate to distant organs via the bloodstream or lymphatic system in the form of tumor cell clusters, where they colonize and form secondary tumors [3].

Tumor cells face a constantly changing microenvironment and energetic stresses, from carcinoma in situ to metastasis via the vasculature or lymphatic system. The foremost challenge is nutrient shortages. The allocation of nutrients in different regions of the human body is limited. This often fails to meet the substantial energy demands of rapidly proliferating tumor cells, thereby impeding their normal metabolism and growth [4]. Moreover, the abundant normal cells surrounding the tumor compete with tumor cells for nutrients, further exacerbating the scarcity of nutrients [5]. Additionally, the metabolic by-products of normal cells can interfere with the metabolic processes of tumor cells. Abnormal vascular distribution leads to a decrease in the transport efficiency of nutrients, which increases the difficulty of nutrient uptake by tumor cells and may also cause spatial heterogeneity in the distribution of nutrients in tumors [6]. During metastasis, flow shear stress in the bloodstream can induce mitochondrial dysfunction and disrupt normal energy metabolism in tumor cells [7]. Finally, the differences in nutrient composition among various tissues can hinder the comprehensive uptake of nutrients by tumor cells, thereby restricting multiple metabolic pathways and leading to energetic stress [8].

In this review, we focus on how different microenvironments impose energetic stresses on tumor cells at various developmental stages and the flexible adaptive mechanisms employed by tumor cells in response. This provides a new perspective for comprehensive research and exploration of therapeutic strategies targeting tumor metabolism.