Telomeres are structurally nucleoprotein complexes at termini of linear chromosomes and
essential to chromosome stability/integrity. In normal human cells, telomere length erodes progressively
with each round of cell divisions, which serves as an important barrier to uncontrolled proliferation
and malignant transformation. In sharp contrast, telomere maintenance is a key feature of human
malignant cells and required for their infinite proliferation and maintenance of other cancer hallmarks
as well. Thus, a telomere-based anti-cancer strategy has long been suggested. However, clinically efficient
and specific drugs targeting cancer telomere-maintenance have still been in their infancy thus far.
To achieve this goal, it is highly necessary to elucidate how exactly cancer cells maintain functional
telomeres. In the last two decades, numerous studies have provided profound mechanistic insights, and
the identified mechanisms include the aberrant activation of telomerase or the alternative lengthening of
telomere pathway responsible for telomere elongation, dysregulation and mutation of telomereassociated
factors, and other telomere homeostasis-related signaling nodes. In the present review, these
various strategies employed by malignant cells to regulate their telomere length, structure and function
have been summarized, and potential implications of these findings in the rational development of telomere-
based cancer therapy and other clinical applications for precision oncology have been discussed.