Engineered bacteria reprogram tumor macrophages and direct copper into cancer cells, triggering cell death and systemic immunity without damaging healthy tissue.
(Nanowerk Spotlight) Tumors do not grow in isolation. They are embedded in a dynamic network of non-cancerous cells, signaling molecules, and structural components—together known as the tumor microenvironment. One of the most influential cell types in this environment is the macrophage, an immune cell typically responsible for clearing pathogens and damaged tissue.
In solid tumors, however, these macrophages are often diverted into a state that protects the tumor instead of attacking it. This altered phenotype is known as the M2 state. M2 macrophages suppress inflammation, encourage tissue remodeling, and facilitate metastasis. Their presence in tumors correlates with worse clinical outcomes.
Converting these cells into their pro-inflammatory counterparts—the M1 phenotype—has been a persistent therapeutic goal. Various approaches have attempted to stimulate this switch, often by using drugs or molecules that exploit the tumor’s own signaling cues. These methods tend to produce inconsistent results, in part because they depend on indirect pathways. Without a means of directly editing the instructions inside macrophages, attempts to control their phenotype remain constrained by the tumor’s unpredictable environment.
Another emerging direction in cancer therapy involves the disruption of copper metabolism. Copper is a trace element essential to many cellular functions, including respiration and antioxidant defense. Cancer cells consume it in elevated amounts to support their rapid growth. Excess copper, however, can induce a regulated form of cell death called cuproptosis.
This process targets mitochondria, degrading proteins that contain iron-sulfur clusters and causing a fatal accumulation of misfolded, copper-bound proteins. The therapeutic use of cuproptosis requires precisely targeted copper delivery, which has proven technically difficult.
Recent advances in synthetic biology and gene editing have opened new options for directly modifying immune cells in tumors. Some bacteria naturally accumulate in tumors due to their preference for oxygen-depleted environments. Genetic engineering allows these organisms to carry therapeutic payloads, including systems for gene editing such as CRISPR-Cas9.
At the same time, nanoparticle design has matured to the point where controlled, localized delivery of metal ions is now feasible. These separate developments have created the conditions for a combined strategy: reprogram macrophages inside tumors and simultaneously redirect copper flow toward cancer cells.
In Advanced Functional Materials (“Genetically Programmable Biohybrid Nanoplatform Enables Cuproptosis‐Immunotherapy via Spatiotemporal Control of Macrophage Polarization and Copper Flux”), researchers from Shandong University and the Chinese Academy of Sciences present a study that introduces a system that uses CRISPR-edited bacteria, combined with copper-carrying nanoparticles, to trigger cell death in tumors while reactivating the immune system. This dual approach reprograms the behavior of macrophages inside the tumor and exploits the resulting changes to initiate copper-driven toxicity in cancer cells.
The engineered system, named BcpDCHD, consists of two coordinated components. The first is a strain of Escherichia coli, modified to carry CRISPR-Cas9 and a guide RNA targeting the gene Pik3cg, which encodes a protein that supports the M2 phenotype in macrophages. Disabling this gene pushes the cells toward the M1 phenotype. The second component is a nanoparticle constructed from human serum albumin bound to copper ions. This structure is coated with polyethylene glycol modified with dimethylmaleic anhydride (DMMA), which remains stable in normal tissue but changes its surface charge under acidic conditions, as found in tumors.
Synthesis process and therapeutic mechanism. Illustrate the synthesis strategy of a) the engineered bio-hybrid material BcpDCHD and its mechanism to precisely intervene in the phenotype and coppermetabolism of M2-TAMs through the “precision editing-metabolism activation-immunity remodeling” cascade pathway to achieve the spatial and temporal synergistic antitumor effects induced by b) cuproptosis in tumors. (Image: Reprinted with permission by Wiley-VCH Verlag) (click on image to enlarge)
To ensure that the bacteria reach macrophages specifically, the authors coated them with dextran, a sugar molecule that binds to receptors found predominantly on M2-type macrophages. Once inside the tumor, the mildly acidic environment triggers the charge reversal of the nanoparticle, improving its uptake by the targeted macrophages. The bacteria then release the CRISPR components, which edit the Pik3cg gene. This genetic modification drives the transition from the tumor-supporting M2 state to the pro-inflammatory M1 phenotype.
The conversion has several consequences. M1 macrophages begin secreting inflammatory cytokines and display markers that support immune activation. At the same time, they increase the expression of copper transport proteins—specifically ATP7A, CTR1, and CTR2. These proteins regulate the uptake and release of copper ions. The M1 phenotype also enhances the expression of CD44, a surface protein that mediates copper uptake through its interaction with hyaluronic acid. Together, these changes create a metabolic environment that directs copper from the immune cells toward the tumor.
When cancer cells absorb this excess copper, it initiates cuproptosis. The process destabilizes mitochondrial metabolism and leads to cell death. In this study, the authors confirmed cuproptosis by measuring the suppression of key enzymes, including lipoyl synthase (LIAS) and ferredoxin 1 (FDX1), as well as increased levels of aggregated proteins. The researchers also observed signs of oxidative stress and mitochondrial dysfunction in tumor cells exposed to the treatment.
The tumor cell death triggered by cuproptosis was immunogenic. That is, it released danger signals that further activated the immune system. These signals included the translocation of calreticulin to the cell surface, release of HMGB1 into the extracellular space, and secretion of ATP. These molecules are known to stimulate dendritic cells, which present antigens to T cells and initiate adaptive immune responses.
In the treated animals, dendritic cell activation increased, along with the number of helper and cytotoxic T cells. At the same time, the proportion of regulatory T cells—those that suppress immune activity—declined.
The authors tested the system in mice with implanted tumors. In single-tumor models, BcpDCHD reduced tumor volume significantly more than control treatments, including versions of the system lacking CRISPR editing or copper delivery. The effect was lost when the animals were given clodronate liposomes, which deplete macrophages, or penicillamine, a copper chelator. This confirmed that the system depends on both macrophage reprogramming and copper-mediated toxicity.
In bilateral tumor models—where one tumor is treated and another is left untouched—the authors observed reduced growth in the untreated tumor, indicating a systemic immune effect. The mice developed higher levels of memory T cells, suggesting the establishment of long-term immune surveillance. Immune markers in the distant tumors confirmed activation of both CD4+ and CD8+ T cells.
The system’s safety profile was also examined. The bacteria preferentially accumulated in the tumor, with minimal presence in the liver, spleen, or other organs. No systemic inflammation or tissue damage was observed. Blood markers remained within normal limits, and the animals maintained stable body weight throughout the study. The CRISPR components remained active in the tumor for at least 15 days, providing a sustained therapeutic window.
BcpDCHD combines direct genetic modification of tumor-associated immune cells with copper delivery that leads to localized tumor cell death. This approach bypasses the need for tumor-derived signals to reprogram macrophages and avoids systemic copper toxicity by restricting its accumulation to the tumor site.
The engineered bacteria act as both delivery vehicle and therapeutic agent, targeting immune cells and enabling a precise cascade of metabolic and immune changes. The result is a platform that aligns gene editing, metabolic disruption, and immune activation into a single intervention.
By designing a system that operates through clearly defined molecular pathways and acts only within the tumor’s microenvironment, the study offers a method of immunotherapy that avoids many of the off-target effects associated with less selective treatments. The demonstration of both local tumor control and systemic immune engagement supports its potential as a base for future combination therapies.
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