Functional dichotomy of autophagy signaling in tumor microenvironment driving hallmarks in oral cancer

Abstract

As a cytoprotective mechanism, autophagy recycles damaged proteins and organelles via the lysosomal degradation pathway in response to diverse stress conditions. However, its role in tumor microenvironment, including oral cancer, is still a point of contention. Although excessive autophagy is associated with cell death, many studies have revealed elevated autophagy levels in advanced stages of oral cancer, providing a suitable niche for growth and proliferation. On the contrary, disruption of basal level autophagy also contributes to oral cancer development at the early stage due to increased oxidative stress and accumulation of genetic mutations. This atypical dependence of oral cancer cells on autophagy is associated with cellular features, stage, and requirements. The present study highlights the involvement of key autophagy-related proteins in oral cancer progression and explores their interaction with oncogenic signaling pathways that drive proliferation, chemoresistance, metabolic reprogramming, and metastasis. Furthermore, increased autophagy in cancer-associated fibroblasts, immune cells, and macrophages within the tumor microenvironment contributes to fibroblast activation, cytokine secretion, and immune suppression, enhancing tumor plasticity. Notably, crosstalk between autophagy and the NLRP3 inflammasome has emerged as a significant factor in promoting oral cancer progression and metastasis. Finally, accumulating evidence supports the therapeutic potential of autophagy modulators, which enhance apoptosis and suppress tumor growth, suggesting that targeting autophagy could offer promising treatment strategies for resistant oral cancers.