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Page 266 Thomas et al. J Transl Genet Genom 2024;8:249-77 https://dx.doi.org/10.20517/jtgg.2024.15

potential to reduce or eliminate tumor-promoting and immunosuppressive properties. However, this
strategy faces challenges due to heterogeneity, phenotypic plasticity, and complex interactions within the
tumor-stroma ecosystem, which can impede the efficacy of the immune response. Understanding and
effectively manipulating these interactions are crucial for the success of DC therapy in targeting the stroma,
potentially leading to more effective control of prostate cancer growth and metastases .
[286]
Despite being generally safe, DC therapy can induce adverse events like flu-like symptoms, injection site
reactions, and potential autoimmunity [287,288] . These adverse events require careful monitoring to ensure
patient safety. In conclusion, while DC therapy in prostate cancer represents a significant advancement in
cancer immunotherapy, it is constrained by challenges such as inconsistent clinical responses, antigen
selection, DC maturation difficulties, immune suppressive TME, transient immune responses, and safety
issues. An important future approach should be focused on identifying biomarkers that could predict
responses to DC therapy, thereby refining patient selection. Additionally, exploring synergies between DC
therapy and other immunomodulatory approaches may unlock new avenues for more effective and
comprehensive cancer treatment strategies.

SUMMARY
The survival of an organism is dependent on the maintenance of robust and dynamic systemic homeostatic
mechanisms regulating physiological responses to both internal stimuli (wound repair, inflammation, and
diseases) and external stimuli (food, pathogens, toxic pollutants, and drugs). Homeostasis is coordinated by
the different functional systems within the body via a multitude of long-range (endocrine), short-range
(paracrine, juxtacrine, neuronal signaling at synaptic junctions), and self (autocrine) cellular signaling. At
the tissue level, the intracellular machinery of tissue-resident cells needs to coordinate and integrate
complex signals from cellular and non-cellular components of the tissue environment. However, in the case
of cancer, accumulating genomic or epigenetic aberrations in cancerous cells can decouple their functional
interactions within a tissue, resulting in the development of neoplasia. Despite the dependence of cancer
cells on multicellular interactions with the respective TME as well as systemic physiological environments,
collectively referred to as "systems biology of cancer", conventional research continues to follow a
reductionist approach, predominantly focusing on cancer-specific intracellular factors, overlooking broader
systems influences on cancer pathobiology [279,280] .

Although localized or locally advanced prostate cancer patients undergo definitive therapy with curative
intent, up to 50% experience recurrence, progressing to mCRPC. While immunomodulatory therapies like
ICIs have advanced as first- or second-line treatments, yielding promising results in various cancers,
including non-small cell lung cancer (NSCLC) and colorectal cancer, their efficacy in advanced prostate
cancer remains limited. Prostate cancer's immunologically "cold" TME underscores the need for a systems
biology approach to identify and characterize spatial and temporal TME signatures. These signatures are
crucial determinants in immunomodulation, disease progression, and treatment response [7,281-283] .

In this review, we have highlighted the critical role of reactive stromal response in the evolution of cancer
pathobiology through immunomodulation of the TME [Figure 2]. The reactive stromal response is an
emergency/emergent response of the tissue to undergo rapid repair and reset homeostasis, a biological
priority. The multifaceted role of reactive stromal cells includes their intercellular communication with
tissue-resident and immune cells in the systemic circulation to enhance tissue repair while minimizing
damage. Thus, to preserve homeostatic balance, the reactive stromal response encompasses immune-
[284]
regulatory functions . Therefore, adopting a cancer systems biology approach is crucial for fully grasping
the dynamic interactions within the reactive/repair-centric TME. This methodology will enable researchers