Tumour-Specific Immunogene Therapy

Tumour-specific immunogene therapy represents an emerging therapeutic paradigm that integrates gene therapy, immunotherapy, and targeted protein delivery to overcome longstanding limitations in the treatment of solid tumors. The central concept is to use immune cells as vehicles to deliver genes encoding therapeutic proteins directly into the tumour microenvironment (TME), thereby achieving high local drug concentrations while minimizing systemic toxicity. This approach addresses two major challenges of solid tumor treatment: inefficient drug penetration into tumors and dose-limiting off-target effects of potent biologics.

Solid tumors are characterized by complex and hostile microenvironments that impede effective therapy. Abnormal vasculature, elevated interstitial pressure, dense extracellular matrix, hypoxia, and immunosuppressive signaling collectively restrict the delivery and activity of conventional protein therapeutics such as cytokines, antibodies, and immune modulators. Systemic administration of these agents often results in inadequate intratumoral exposure while causing significant toxicity in normal tissues. Tumour-specific immunogene therapy aims to bypass these barriers by enabling in situ production of therapeutic proteins within the tumor itself.

At the core of this strategy is the genetic modification of immune cells—most commonly T lymphocytes, natural killer (NK) cells, macrophages, or dendritic cells—to express and secrete therapeutic proteins selectively at tumor sites. These immune cells possess intrinsic tumor-homing properties, guided by chemokines, adhesion molecules, and antigen recognition. By engineering them to carry therapeutic genes, they become “living factories” that continuously produce biologically active proteins precisely where they are needed.

One of the most developed platforms for tumour-specific immunogene therapy involves chimeric antigen receptor (CAR) T cells or T-cell receptor (TCR)-engineered T cells that are further modified to secrete immunomodulatory proteins. In this context, the immune cell’s antigen specificity directs it to the tumor, while the encoded protein reshapes the surrounding microenvironment. For example, CAR-T cells engineered to secrete interleukin-12, interleukin-18, or interleukin-15 can locally enhance immune activation, recruit endogenous immune cells, and counteract immunosuppressive signals such as regulatory T cells or myeloid-derived suppressor cells. Importantly, local secretion limits systemic cytokine exposure, reducing the risk of severe toxicity.

Macrophages are also attractive vehicles for immunogene therapy, particularly in solid tumors where tumor-associated macrophages (TAMs) are abundant. Genetic reprogramming of macrophages can convert them from an immunosuppressive, tumor-promoting phenotype into pro-inflammatory, tumoricidal cells. Engineered macrophages can be designed to secrete cytokines, enzymes that remodel the extracellular matrix, or antibodies that block immune checkpoints. Their natural ability to infiltrate hypoxic and poorly vascularized tumor regions makes them especially valuable for delivering protein therapeutics to areas inaccessible to other modalities.

Another important application is the delivery of immune checkpoint inhibitors directly within the tumor microenvironment. Instead of systemic administration of monoclonal antibodies against PD-1, PD-L1, or CTLA-4, immunogene-modified cells can produce these inhibitors locally. This strategy enhances antitumor immune responses while minimizing immune-related adverse events in healthy tissues. Similarly, engineered immune cells can secrete bispecific antibodies or antibody fragments that engage tumor cells and immune effector cells simultaneously, amplifying localized cytotoxicity.

Beyond immunomodulatory proteins, tumour-specific immunogene therapy can deliver cytotoxic or pro-apoptotic proteins. These include death ligands such as TRAIL, enzymes that activate prodrugs, or toxins under tightly regulated promoters. By confining expression to the tumor microenvironment, these potent agents can be used safely, achieving levels of tumor cell killing that would be intolerable if administered systemically.

The specificity of immunogene therapy is achieved through multiple layers of control. Targeting begins with the intrinsic homing and antigen recognition properties of immune cells. Additional specificity can be engineered at the genetic level using tumor-responsive promoters, synthetic gene circuits, or logic-gated systems that require multiple tumor-associated signals for activation. For example, gene expression can be restricted to hypoxic conditions, inflammatory cytokine gradients, or the presence of specific tumor antigens. These safeguards reduce the risk of off-tumor effects and improve the therapeutic index.

Gene delivery methods for immunogene therapy typically involve viral vectors, such as lentiviruses or retroviruses, which enable stable integration and long-term expression of therapeutic genes in immune cells. Non-viral approaches, including transposon systems and mRNA electroporation, are also being explored to improve safety and flexibility. Advances in synthetic biology have enabled the construction of sophisticated genetic programs that allow immune cells to sense their environment and respond dynamically by producing therapeutic proteins only when appropriate.

Despite its promise, tumour-specific immunogene therapy faces several challenges. The immunosuppressive nature of the tumor microenvironment can impair immune cell survival and function, limiting the duration of protein delivery. Antigen heterogeneity and loss can reduce targeting efficiency, particularly for CAR-based approaches. Manufacturing complexity and cost remain significant barriers, as therapies often require personalized cell engineering. Additionally, careful control of protein expression levels is essential to avoid local toxicity or excessive inflammation within the tumor.

Clinical translation of tumour-specific immunogene therapy is advancing, with early-phase trials exploring armored CAR-T cells, cytokine-secreting immune cells, and macrophage-based therapies in solid tumors. While most data are still preliminary, these studies demonstrate the feasibility of localized protein delivery and provide early signals of enhanced antitumor activity compared with conventional approaches.

In summary, tumour-specific immunogene therapy offers a powerful strategy to deliver protein therapeutics directly to solid tumor microenvironments by harnessing the targeting capabilities of immune cells and the precision of genetic engineering. By enabling localized, sustained production of potent biologics within tumors, this approach addresses key limitations of systemic protein therapy and opens new avenues for treating solid malignancies that have historically been resistant to immunotherapy. As vector design, synthetic gene circuits, and cell engineering technologies continue to mature, tumour-specific immunogene therapy is poised to become a critical component of next-generation cancer treatment.