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Page 258 Thomas et al. J Transl Genet Genom 2024;8:249-77 https://dx.doi.org/10.20517/jtgg.2024.15

Endothelial cell memory
Similar to fibroblasts, EC is also activated in response to inflammation. EC activation can be distinguished
as a "delayed (type II)" or "immediate (type I)" response. In the delayed response, upon activation, EC
expresses chemokines, VCAM-1, intercellular adhesion molecule (ICAM-1), and E-selectin several hours
post-stimulus due to a requirement for de novo transcription and translation [137,138] . In contrast, in the type I
response, there is no delay following stimulation and response due to the preformation of adhesion
molecules and chemoattractant resulting from a preceding inflammatory stimulus. This suggests EC
memory [138-141] . Studies have demonstrated that EC exposed to homocysteine, an independent risk factor for
developing atherosclerosis, has an augmented response to inflammatory mediators such as LPS and
thrombin . Additionally, recent studies have also shown that EC stores a metabolic memory of an earlier
[142]
transient hyperglycemia in the vasculature in diabetic patients, resulting in epigenetic changes,
cardiovascular complications, chronic inflammation, and oxidative stress in later stages [143-145] .

As integral components of the tissue structure, the ability of stromal cells to adapt to environmental stimuli
while retaining memory of past exposures is essential for maintaining tissue homeostasis [125,146,147] . Various
environmental stimuli, such as injury or infection, can trigger the innate cellular memory in stromal cells,
leading to an activated phenotypic and functionally emergent state through different molecular
mechanisms, as described. This emergent microenvironment state of tissues in diseases like cancer can have
a detrimental impact on disease initiation and development, progression, and response to
treatments [21,125,148-150] . For instance, chronic inflammation of organs due to injury-causing agents or
infections is known to induce cancers, such as esophageal, lung, gastric, and colon cancer, which are often
metastatic, treatment-resistant, and lethal [151-158] . Therefore, targeting specific stromal memories involved in
maintaining a reactive/emergent stromal response emerges as a promising therapeutic strategy to mitigate
the detrimental effects of microenvironment priming and enhance treatment efficacy in cancer
patients [21,125,159] .

IMMUNE REGULATION IN CANCER
Traditionally, cancer research has focused on the intrinsic biology of cancer cells to identify potential
molecular determinants crucial for tumor growth, development, and progression. However, there has been
a recent shift in attention toward the role of non-cancerous cellular components in the TME, particularly
immune cells, in controlling tumor growth and development. This shift has been clinically validated and
garnered attention because of its potential to be curative in subsets of cancer patients . Consequently,
[150]
there has been an increase in research efforts aimed at understanding the mechanisms regulating the
reactivity of immune cells toward various types of tumors. This shift in focus reflects a growing recognition
of the intricate interplay between cancer cells and the TME, highlighting the importance of
comprehensively understanding the latter for the development of effective cancer therapies.

Paul Ehrlich's hypothesis on immune cells suppressing carcinoma development led to the "immune
[160]
surveillance hypothesis" later proposed by Burnet and Thomas . While the tumor-specific immune
response was validated in inbred mouse strains, discordant results from immune-deficient mouse models
initially cast doubt on the concept . However, the development of defined immune-deficient models and
[161]
epidemiological data from human studies reaffirmed the relevance of cancer immune surveillance, leading
to the broader concept of "cancer-immuno-editing". This concept recognizes the dual role of host-
protecting and tumor-sculpting properties of the immune system. Cancer-immuno-editing involves three
stages: tumor elimination by the immune system (immune surveillance), a phase of equilibrium where