Active autophagy in cancer‐associated fibroblasts: Recent advances in understanding the novel mechanism of tumor progression and therapeutic response

Abstract

Autophagy is primarily a homeostatic and catabolic process that is increasingly being recognized to have a pivotal role in the initiation and maintenance of cancer cells, as well as in the emergence of therapeutic resistance. Moreover, in the tumor microenvironment (TME) autophagy plays a crucial and sometimes dichotomous role in tumor progression.Recent studies show that during the early stages of tumor initiation, autophagy suppresses tumorigenesis. However, in the advanced stage of tumorigenesis, autophagy promotes cancer progression by protecting cancer cells against stressful conditions and therapeutic assault. Specifically, in cancer-associated fibroblasts (CAFs), autophagy promotes tumorigenesis not only by providing nutrients to the cancerous cells but also by inducing epithelial to mesenchymal transition, angiogenesis, stemness, and metastatic dissemination of the cancer cells, whereas in the immune cells, autophagy induces the tumor-localized immune response. In the TME, CAFs play a crucial role in cancer cell metabolism, immunoreaction, and growth. Therefore, targeting autophagy in CAFs by several pharmacological inducers like rapamycin or the inhibitor such as chloroquine has gained importance in preclinical and clinical trials. In the present review, we summarized the basic mechanism of autophagy in CAFs along with its role in driving tumorigenic progression through several emerging as well as classical hallmarks of cancer. We also addressed various autophagy inducers as well as inhibitors of autophagy for more efficient cancer management. Eventually, we prioritized some of the outstanding issues that must be addressed with utmost priority in the future to elucidate the role of autophagy in CAFs on tumor progression and therapeutic intervention.

Targeting the tumor stroma for cancer therapy

“…Then, in response to changes in the TME, these CAFs secrete pyruvate and lactate that can be used by epithelial cancerous cells to generate energy and enhance their proliferative capacity via oxidative phosphorylation (OXPHOS) [140]. The metabolism of tumor cells is also influenced by CAFs-modulated autophagy and oxidative stress pathway to promote tumor cell proliferation and drug resistance [141][142][143][144][145].…”

Determining the Mechanism of Banxia Xiexin Decoction for Gastric Cancer Treatment through Network Analysis and Experimental Validation

“…Autophagy has different effects on tumors under different circumstances . On the one hand, basal autophagy is considered an important factor in inhibiting cancer development, and its ability to remove damaged mitochondria can reduce reactive oxygen species production and thus inhibit tumor generation and progression. , but on the other, autophagy can provide the required energy for tumor cells and further promote tumor development . Therefore, regulation of autophagy can be an effective strategy for cancer treatment.…”

Identification of an Autophagy-Related lncRNA Prognostic Signature and Related Tumor Immunity Research in Lung Adenocarcinoma

“…For example, TMB and TIME were identified as important determinants of the efficacy of ICIs and in the prognosis of cancer patients ( Wu et al, 2021b ). Moreover, Jena et al (2021) have demonstrated that autophagy was closely related to TIME and participated in tumor progression. To explore the relationship between the ARlncRNA signature and tumor immunity thoroughly, we conducted ssGSEA to investigate the immune status in different groups.…”