How Mitochondrial Vesicle Miscommunication May Allow Cells to Evade Immune Surveillance
Jeya Chelliah B.Vsc Ph.D.
Exploring a Hypothetical Oncogenic Pathway Hidden in Plain Sight
In cancer biology, the focus has long been on genetic mutations, epigenetic alterations,
and environmental exposures that tip the balance from a normal to a malignant cell.
However, not all cancer initiation events can be explained by DNA mutations alone.
Emerging research suggests that non-genetic and non-mutational early events, especially
involving organelle communication and immune crosstalk, may play a role in oncogenesis.
In this blog, we introduce a hypothetical but biologically plausible pathway that may
allow a cell to silently become cancerous by evading early immune detection — not
through mutational escape, but through a failure in mitochondrial vesicle signaling. We call
this model the Mito-Immune Feedback Loop Failure (MIFLF) hypothesis.
This pathway posits that subtle mitochondrial dysfunctions in cells lead to the release of
specialized mitochondrial-derived vesicles (MDVs) carrying early danger signals. In healthy
cells, these MDVs may help recruit innate immune surveillance mechanisms. However,
when this communication fails—either due to mutations, stress-adaptive bypasses, or
immune receptor desensitization—the cell continues to survive, rewires its metabolism,
and begins drifting toward a cancerous fate. Importantly, this bypasses classical immune
recognition, allowing these cells to fly under the immune radar during the earliest stages of
transformation.
Step-by-Step Hypothetical Pathway: The MIFLF Model
1. Mild Mitochondrial Stress and mtDNA Damage
Early in carcinogenesis, cells accumulate minor mitochondrial DNA (mtDNA)
mutations due to oxidative stress or environmental toxins. These do not induce cell
death but subtly impair electron transport and ATP synthesis, leading to metabolic
imbalance and reactive oxygen species (ROS) production.
2. Formation and Release of Mitochondrial-Derived Vesicles (MDVs)
In response to mitochondrial stress, cells generate MDVs — small vesicles that bud
off from mitochondria, carrying damaged proteins, lipids, or fragments of mtDNA. In
some studies, these vesicles have been shown to interact with lysosomes or be
secreted into the extracellular space.
3. Immune Sensing via cGAS-STING or RIG-I Pathways
Normally, extracellular mtDNA or mitochondrial RNA fragments are sensed by
immune pattern recognition receptors (PRRs) such as cGAS-STING, RIG-I, or TLR9,
which trigger type I interferon responses and recruit immune cells to assess cell
integrity.
4. Signal Integration Failure in At-Risk Cells
In certain cells, we hypothesize the presence of an uncharacterized regulatory
mechanism (which we term MTVSIG: Mitochondrial Vesicle Signal Integration
Gatekeeper) that either suppresses MDV generation, blocks PRR activation, or
prevents MDV cargo from being recognized. This could be due to epigenetic
silencing, post-translational modifications, or microRNA regulation that degrades
vesicle-associated signals.
5. Silent Progression to Immunologically ‘Cold’ State
With the immune system failing to detect these stressed cells, they begin to adapt
to their altered metabolic state. Over time, these cells shift toward aerobic
glycolysis (Warburg-like metabolism), become more resistant to apoptotic signals,
and upregulate survival pathways — all without triggering immune alert.
6. Clonal Expansion and Full Malignancy
Eventually, these immune-evading pre-cancerous cells acquire additional genomic
or epigenomic changes, enabling angiogenesis, immune suppression, and tissue
invasion — hallmarks of full-blown cancer.
Why This Hypothetical Pathway Is Plausible
Several findings in recent years support the plausibility of this proposed pathway, even
though the full MIFLF model has never been explicitly described:
• Mitochondrial vesicle trafficking is real. Studies have shown that mitochondrialderived vesicles can carry oxidized cargo to lysosomes for degradation or be
released extracellularly (Sugiura et al., Nature 2014).
• Mitochondrial nucleic acids are immune-stimulatory. Cytosolic or extracellular
mtDNA can activate cGAS-STING and induce interferon responses (West et al., Cell
2015).
• Immune failure precedes cancer in some models. There is growing recognition
that tumors often emerge in immune-privileged environments or where innate
immunity is suppressed (Chen and Mellman, Immunity 2017).
Yet despite these clues, scientists may have overlooked this pathway because:
• The MDV field is still niche, and not fully integrated into mainstream cancer
biology.
• Most researchers focus on macrophages, dendritic cells, and T cells as the
immune gatekeepers, ignoring cell-intrinsic early warning systems.
• The immune system is usually studied in the context of infection or full-blown
tumors, not in silent pre-malignant cell states.
Breakthrough Potential in Cancer Research
If validated, the MIFLF pathway offers a radical shift in how we understand immune escape
during the earliest steps of transformation. It suggests that cancer may not always start
with DNA damage or inflammation, but from an unnoticed mitochondrial whisper — a
failed vesicular cry for help that went unheard. Therapeutically, this could mean:
• Reactivating immune sensors of mitochondrial vesicle signals could restore
immune detection of pre-cancerous cells.
• Early screening for vesicle signal disruption could detect cancers before
mutation burden is high.
• Targeting MTVSIG-like regulatory checkpoints could prevent immunologically
silent transformation altogether.
How to Test This Hypothesis in the Lab
To explore this pathway experimentally, scientists could design the following studies:
1. Induce mild mitochondrial stress in normal epithelial cells using low-dose ROS or
sub-lethal toxins (e.g., rotenone), and track MDV release.
2. Label and track MDVs using fluorescent lipid dyes or mitochondrial-targeted
reporters.
3. Co-culture these cells with immune cells (e.g., macrophages, dendritic cells) and
assess PRR activation (cGAS-STING pathway, IFN-β production).
4. Genetically silence candidate genes suspected to regulate MDV formation or
immune sensing (e.g., SNX9, VPS35, TOMM20 variants) and observe whether
immune activation is suppressed.
5. Use single-cell RNA-seq to detect early immune evasion signatures or metabolic
rewiring in these cells over time.
6. Test for tumorigenic potential of these cells in immunocompetent vs.
immunodeficient mice.
The MIFLF hypothesis presents a speculative, but biologically grounded mechanism for
early immune evasion in cancer. By spotlighting the role of mitochondrial-derived vesicles
and their failure to communicate stress to the immune system, this model opens a fresh
dimension of investigation into how cancers silently begin. As our tools for tracing interorganelle and cell-to-immune interactions improve, it may be only a matter of time before
this hidden conversation — or its breakdown — is proven to be a critical event in cancer
initiation.