The Inflammasome and Pyroptosis
The immune system has a powerful emergency mechanism designed to respond to serious cellular damage—but cancer can hijack that response and turn it into a source of its own survival. This page explores the inflammasome and pyroptosis, revealing how a process meant to trigger inflammation, eliminate damaged cells, and activate immune defenses can become chronically activated inside a tumor, fueling blood-vessel growth, immune suppression, tissue remodeling, invasion, and metastasis. From NLRP3 and IL-1β to emerging research on pancreatic, breast, and colorectal cancers, the story raises an important question: can we disrupt the inflammatory machinery that cancer has learned to control while preserving its essential role in healthy tissue repair?
Introduction
The established presence of a tumor within the body potentially changes the normal protective terrain into a tumor-controlled microenvironment. It hijacks the ecosystem and creates its own diverse subsets of cancer cells, dysregulates the immune system, promotes chronic, persistent, robust inflammation, stimulates new blood vessel growth, and supports matrix remodeling. Its ultimate goal is to prevent constraints on growth and metastasis, ensuring survival.
A tumor-controlled microenvironment (TME) provides conditions that allow cancer cells to thrive, expand, and evolve. A key component requires the perpetuation of chronic, enduring inflammation caused by ongoing cellular damage and/or stress.
Normally, injury or cell damage detected by the innate immune system, primarily macrophages, neutrophils, and dendritic cells, activates an acute response designed to contain and resolve the inflammation and damage and allow healing. One prominent mechanism that assists is apoptosis, a non-inflammatory form of cell death that removes cellular damage to reduce continued stimulation by the immune system, which would promote an ongoing inflammatory response. Normally, apoptosis assists in resolving inflammation and provides a needed function of preventing inflammasome activation.
The inflammasome is an emergency, transient response to cellular stress or danger designed to create strong inflammation. If tissue damage is severe and cells are beyond recovery, the immune system will use the inflammasome to activate pyroptosis, an intense inflammatory response that lyses cells and releases cytokines and damage substances called damage-associated molecular patterns, DAMPs.
These pathways, apoptosis and the inflammasome, intersect via the caspase system, a family of protease enzymes that break down proteins into smaller units, peptides. Caspases-3 and 6-8 initiate apoptosis, while, if the situation reflects greater damage, caspase-1 triggers this marked inflammatory response.
Established tumors are able to manipulate and avoid the normal responses needed for de-escalating inflammation and initiating repair by hijacking control of the terrain and adapting it to create a tumor environment that actually sustains cell damage and persistent, ongoing inflammation.
It is important to understand that the initial response to cellular and tissue injury, both normally and by the tumor, is similar, but the direction taken determines whether the damage is controlled and normal function restored or involves the tumor chronically reprogramming the environment to resemble a non-resolving wound, without resolution.
In acute situations, or early cancer, the inflammasome/pyroptosis response can eliminate abnormal cells, release antigens for immune recognition and removal, and activate cytotoxic CD8 T cells. But chronically, in a disease like cancer, this protective mechanism becomes persistent, intensified, and commandeered by the cancer to become tumor-promoting.
The Normal Inflammasome Response
When the body senses significant tissue damage and danger signals resulting from dying cells releasing damage-associated molecular patterns, DAMPs:
Cytokines become activated by the inflammasome; IL-1B and IL-18 are produced to help in repair by recruiting needed immune cells.
Recruitment of immune cells as the front-line defense via macrophages and dendritic cells is followed by the adaptive immune response of natural killer cells to remove damage, repair wounds, and/or clear infection.
With repair, fibroblasts create collagen with other structural substances to assist in matrix remodeling.
The epithelial-mesenchymal transition, EMT, program allows epithelial cells to loosen their bonds, change position, become mobile, and travel to other areas. In normal repair, they are able to transition into needed types of repair cells and migrate to needed areas for wound healing.
In normal healing, the inflammasome is designed to address severe inflammation, so with resolution and equilibrium reestablished, the response ends.
Inflammasome Assembly
Damage Sensors
Immune cells have a group of sensors, called nucleotide-binding domain-like receptors (NLRs), which are complex proteins that are intracellular, especially in macrophages and monocytes. NLRP3 is one NLR protein, stimulated by inflammation and the most important sensor for responding to damage/injury/cellular distress.
Adaptor
The adaptor stage is then used in the assembly of the inflammasome. When the NLRP3 sensor becomes activated, it recruits the adaptor protein apoptosis-associated speck-like protein (ASC), which acts to amplify the sensor connection but also provides additional binding sites called the caspase recruitment domain (CARD), which then recruits pro-caspase-1, the inactivated caspase enzyme.
Caspase-1 Activation
This occurs as the enzyme pro-caspase-1 is then activated and generates active caspase-1.
Once this activation occurs, the inactive cytokines pro-IL-1B and pro-IL-18 are converted to active forms, IL-1B and IL-18. Caspase-1 also activates gasdermin D, which binds to the cell membrane and creates pores that allow IL-1B and IL-18 cytokines to enter, causing cells to rupture in a process called pyroptosis.
In acute situations, inflammasome activation, while normal, is a temporary response, but in cancer, the activation becomes persistent and prolonged, promoting continued terrain damage.
Sequence of Events
Increase in production of inactive inflammasome elements, NLRP3 protein, IL-1B, and IL-18
ASC recruitment
Assembly of NLRP3 plus the adaptor plus pro-caspase-1
Caspase-1 activation
Gasdermin D activated and pores formed
Release of IL-1B, IL-18, and water enters the cell
Pyroptosis
Inflammasome Activation
When the inflammasome is activated, rather than slow, ongoing inflammation, the immune system supercharges an amplified, escalated response through activation of caspase-1.
In a normal setting, the inflammasome amplifies inflammation and recruits additional immune cells to remove damaged or abnormal cells and initiate repair.
When tumor growth increases, damage/danger signals increase because it produces low oxygen, deficient nutrients for growth, oxidative stress, low pH, mitochondrial damage, the release of ATP, and inflammatory cell death. So the inflammasome is activated because it detects damage, not because it is attacking the cancer.
Chronic Maintenance of Persistent Inflammation by the Tumor
Secondary to its growth, tumors both generate significant danger signals and inflammatory responses but are designed with the strategy of programming them to be used to benefit tumor growth and spread.
In this setting:
Cellular death, low oxygen levels, oxidative damage, and abnormal metabolic products are all manipulated to support continued inflammation, not healing.
Tumors modify themselves to resist resolution by apoptosis or pyroptosis.
Tumor cytokines recruit marrow-derived suppressor cells, MDSC cells, through signals to the bone marrow, which alter normal immune maturation and create cell types that are immunosuppressive and act to suppress natural killer (NK) and cytotoxic T cells.
Tumors promote new blood vessel growth and change normal macrophages into tumor-associated macrophages, TAMs, that inhibit both CD8 T cytotoxic cells and NK cells
and produce growth factors for the tumor that suppress immune responses.
Tumors persistently commandeer fibroblasts and the supportive matrix, adapting it to allow growth and angiogenesis, or new blood vessels, to allow tumor invasion.
EMT, which allows limited travel normally for repair, becomes engaged permanently to allow tumor cells to move, invade, and metastasize.
Tumors block resolution of inflammation to prolong healing and repair and allow more tumor growth, making cancer the wound that doesn't heal. (See the in-depth article on this topic here on the website.)
Current Research
Oncology Research
The objective of treatment innovation in medical oncology is focused on:
Targeting the immune cells, mainly the TAMs, to disrupt their signaling, which can be more effective than targeting the tumor.
Directly activating the inflammasome within the tumor itself to induce pyroptosis inside the cancer cells
Additional Research
NLRP3 and Pancreatic Ductal Adenocarcinoma (PDAC)
In pancreatic ductal adenocarcinoma, tumor cell-derived proinflammatory IL-1B helps stimulate a tumor microenvironment that promotes the transformation of normal cells into cancer cells and, at the same time, initiates an immunosuppressive terrain with proinflammatory cells, using M2 macrophages, regulatory B cells, and T17 helper cells.
In addition, upregulation of IL-1B occurs in several cancers, including head and neck, breast, lung cancers, and melanoma, and it is associated with poorer prognosis by sustained activation of NF-kB, which supports cytokine production, and mitogen-activated kinase (MAPK) pathways, which increase cancer proliferation.
The study by Drs. Das, Shapiro, and Bar-Sagi, published in Cancer Research (2020), demonstrated that the pancreatic ductal adenocarcinoma tumor cell-derived proinflammatory cytokine IL-1B is necessary for the development of a tumor microenvironment that supports tumor growth. It promotes immunosuppression mediated by myeloid-derived cells, M2 macrophages, and inhibits anti-tumor immune reactions. IL-1B also recruits tumor-associated macrophages (TAMs), which produce growth factors for the tumor, suppress immune responses, and support new blood vessel growth to allow spread.
Using a mouse model, the researchers showed that the loss of IL-1B signaling in the microenvironment of PDAC allowed reactivation of CD8 cytotoxic T cells and enabled enhanced survival of the PDAC-bearing mice.
Breast Cancer
In animal and human models, Dr. Guo and Fu demonstrated in the journal Scientific Reports that mice made deficient in inflammasome components had diminished breast cancer tumor growth. Also, inflammasome activation of IL-1B promoted infiltration of bone marrow-derived myeloid tumor suppressor cells and tumor-associated macrophages (TAMs) into the tumor microenvironment, which would support cancer growth.
To counteract these inflammasome effects that favor tumor growth, their research demonstrated that blocking the IL-1 pathway inhibited effects of tumor growth and spread.
This study by Drs. Jin, Fuchs, and others measured IL-1B in tissue extracts from >200 breast cancer patients. IL-1B was detected in 90% of invasive breast cancers at a much higher level than in lower-risk breast ductal carcinoma in situ (DCIS) and benign lesions. This finding also suggested breast cancer could be more aggressive in the presence of IL-1B in estrogen receptor (ER) negativity, high-grade tumor, and p53 positivity.
Their conclusions suggested that IL-1B was found in the microenvironment of most breast cancers and higher levels were associated with tumor aggressiveness and a greater ability to invade.
Colitis-Associated Cancer
A study using a mouse model of colitis demonstrated that inflammatory neutrophils produce large amounts of IL-1B that are associated with development of colitis-associated colon cancer. Decreasing these neutrophils by blocking IL-1B substantially reduced damage to the mucosal lining and the development of cancer. The conclusion was that in colitis-associated cancer, IL-1B promotes the growth of cancer.
Research
In a recent focus discussion with oncologists, their discussion suggested that a focus of cancer research was on modulating IL-1B. And indeed, there is research being funded currently for IL-1B inflammasome blockers to target the inflammatory process in the tumor microenvironment and impact cancer outcomes.
Anakinra, an IL-1 receptor antagonist which is used in rheumatoid arthritis, is now being studied in combination with other chemotherapies for acute myelogenous leukemia, colorectal and prostate cancer, and multiple myeloma. Also, early trials for breast and pancreatic cancer are being initiated.
Canakinumab, a monoclonal antibody used as an IL-1 blocker, is showing effects in reducing mortality in lung cancer patients by slowing tumor growth, reducing inflammation, and preventing greater tumor invasiveness.
Currently there are Phase 3 trials, with these drugs, for non-small cell lung cancer combined with immune checkpoint drugs.
Other early trials are ongoing for triple-negative breast cancer and colorectal cancer.
The goals of these clinical trials with IL-1B-inhibiting drugs are to ascertain:
Can they regulate the tumor microenvironment?
How do they work with PD-1 immune checkpoint inhibitors?
Do they help prevent metastasis?
Integrative Approaches to Block Inflammasome Triggering
Curcumin
In multiple studies, curcumin was shown to reduce IL-1B and inhibit caspase-1.
Omega-3 Fatty Acids
A study found omega-3 fatty acids inhibited NLRP3 activation and decreased inflammatory dysfunction in a mouse model by reducing inflammasome assembly. From the journal Immunity, June 2013.
Resveratrol
Inhibits NLRP3 activation and protects mitochondria. ScienceDirect, August 2020, by Drs. Olcum, Tastan, Genc, and others.
It was also shown in multiple other scientific studies.
Quercetin
In multiple studies, quercetin reduced NLRP3 expression and caspase-1 production.
EGCG
In multiple studies, it reduced IL-1B and caspase-1.
Ginseng
Ginseng was shown to reduce IL-1B in two studies.
Sulforaphane
In multiple studies, sulforaphane reduced IL-1B and caspase-1.
Please see the accompanying article for a more in-depth explanation of the tumor microenvironment, TME, and preventive concepts and measures to reduce its effects.
It is important to recognize that the tumor microenvironment is not just triggered by the cancer but develops within the body and actually is initiated by earlier disruptions in the terrain that allow cancer development and then support its growth.
Integrative Perspectives
Chronic inflammation initiated by the tumor alters and disrupts the normal terrain and assists in establishing a supportive tumor microenvironment, enhancing survival. A strong "inner terrain," or internal ecosystem, plays a crucial role in defending against cancer and reduces the risk of many other chronic degenerative diseases.
Acknowledging this direct association between persistent inflammation and disease suggests that interventions devised to reduce other potential causative sources are extremely beneficial.
If cancer prefers and attempts to create chronic, persistent inflammation, and the body is already exhibiting this desired environment, cancer can take advantage and utilize these existing conditions to its advantage.
The contribution of environmental toxicants and hidden pathogens are increasingly recognized as potential factors associated with cancer initiation and recurrence caused by their generation of chronic inflammation as well as epigenetic effects.
Our daily lives involve constant exposure to potentially hazardous substances, from plasticizers, petrochemicals, and forever chemicals to preservatives, pesticides and herbicides, heavy metals and solvents, and water and air pollutants (indoor and outdoor). Lifestyle factors, such as excessive alcohol consumption and smoking, are also noted as significant contributors to chronic inflammation.
While not directly treating cancer, the article proposes that uncovering and addressing these underlying issues could provide valuable supportive care in cancer treatment and prevention.