THERAPEUTIC HORIZONS OF AUTOPHAGY AND APOPTOSIS IN COLORECTAL CANCER: A TRANSLATIONAL PERSPECTIVE FROM MOLECULES TO MEDICINE

Abstract

Autophagy and apoptosis are fundamental cellular processes that profoundly influence colorectal cancer (CRC)
development, progression, and response to therapy. As our molecular understanding of these pathways has deepened, so
too have efforts to exploit them for therapeutic benefit. This review provides a comprehensive overview of autophagy
and apoptosis mechanisms in CRC, highlighting key regulatory molecules and crosstalk between the pathways, and
examines current and emerging therapeutic strategies that target these processes – from bench to bedside. We discuss
how autophagy can act as both a tumor suppressor and a resistance mechanism in CRC, the frequent dysregulation of
apoptosis pathways (e.g., p53 mutations, Bcl-2 family overexpression) that allows colorectal tumor cells to evade cell
death, and how these insights are guiding translational research. Therapeutic agents that modulate autophagy (such as
chloroquine derivatives, mTOR inhibitors, and novel autophagy inhibitors) and those that promote apoptosis (including
BH3 mimetics targeting Bcl-2 family proteins, death receptor agonists, and p53 reactivators) are critically reviewed.
Preclinical studies demonstrate that inhibiting autophagy can sensitize CRC cells to chemotherapy-induced apoptosis,
and conversely, promoting autophagic flux under certain conditions can drive type II cell death. The translational
pipeline features several combination approaches – for example, trials of hydroxychloroquine with chemotherapy to
overcome treatment resistance, and BH3 mimetic drugs to restore apoptotic potential in refractory CRC. We also explore
how autophagy and apoptosis modulation intersect with other modalities like immunotherapy (e.g., autophagy influences
immunogenic cell death and antigen presentation) and targeted therapies (e.g., oncogenic signaling inhibitors may induce
compensatory autophagy). By integrating preclinical data with clinical trial results, we outline the “therapeutic horizons”
wherein manipulating cell death pathways could improve outcomes for CRC patients. This includes a look at precision
medicine approaches: selecting patients based on biomarkers such as Bcl-2 family expression profiles or autophagy
activity for tailored therapies. In summary, the translation of molecular insights in autophagy and apoptosis into clinical
interventions is underway, holding promise for new treatments that can effectively eliminate colorectal cancer cells by
tipping the balance from survival to death.