Subcutaneous Immunotherapy vs Intravenous Immunotherapy in Cancer: Mechanisms, Clinical Trials, and Future Potential

Subcutaneous immunotherapy (SCIT), traditionally used to treat allergic conditions through repeated administration of specific antigens, is now being repurposed in oncology as a novel route for immune activation against cancer. While systemic and intratumoral immunotherapies have dominated the field, SCIT offers a unique mode of immune modulation—targeting dermal antigen-presenting cells to induce durable, tumor-specific T cell responses.

As the search for more tolerable, effective, and accessible cancer immunotherapies continues, SCIT has emerged as a promising strategy, particularly in cancer vaccine delivery and cytokine-based immune stimulation. This article reviews the scientific basis of SCIT in oncology, outlines key clinical and translational advances, and discusses its potential to complement and enhance existing immunotherapeutic modalities.

Repurposing Subcutaneous Immunotherapy for Cancer

Subcutaneous immunotherapy (SCIT) has been a proven strategy in allergology, effectively inducing long-term tolerance to allergens like pollen and venom through repeated subcutaneous injections. Its mechanism—modulating dendritic cells and generating antigen-specific regulatory T cells—has made it an appealing model for cancer immunotherapy.

In oncology, SCIT is now being reimagined not to induce tolerance but to stimulate robust anti-tumor immune responses. By delivering tumor-associated antigens or neoantigens subcutaneously, often with adjuvants like GM-CSF, researchers aim to enhance T cell priming in a controlled, localized manner.

SCIT’s use in cancer began with early peptide vaccine trials in the 1990s. Over time, its role expanded with the development of personalized neoantigen vaccines and subcutaneous cytokine delivery. Today, SCIT is emerging as a practical and immune-potent route to support cancer vaccines, immune modulators, and combination therapies—bridging lessons from allergy to oncology.

Mechanisms of Action in Cancer: The Immunologic Basis of Subcutaneous Delivery

Subcutaneous immunotherapy activates the immune system through a series of well-orchestrated steps:

• Antigen uptake by dermal dendritic cells (DCs): Tumor antigens delivered subcutaneously are rapidly captured by skin-resident dendritic cells.

• Migration via lymphatics to draining lymph nodes: Activated DCs travel through lymphatic vessels to regional lymph nodes, where they present antigens to naïve T cells.

• T cell priming and cross-presentation: Within the lymph nodes, dendritic cells cross-present tumor-associated antigens to CD8+ T cells, promoting cytotoxic T cell activation.

• Memory T cell generation: In addition to immediate effector cells, this process supports long-term memory T cell formation, essential for sustained tumor control.

• Local immune activation with adjuvants: Co-administered agents like GM-CSF, CpG (TLR9 agonist), or other TLR agonists enhance dendritic cell activation and amplify the immune response at the injection site.

• Controlled and safe immune engagement: Unlike intravenous (IV) therapies, SCIT offers lower systemic exposure and reduced toxicity. Compared to intratumoral (IT) routes, it doesn’t require direct access to tumors and is easier to administer.

This mechanism supports SCIT as a powerful platform for cancer immunotherapy—capable of initiating strong, targeted immune responses with improved safety and accessibility.

Cancer Applications of Subcutaneous Immunotherapy

Subcutaneous immunotherapy is emerging as a powerful vehicle for cancer vaccines. In melanoma, Moderna’s personalized neoantigen mRNA‑4157 vaccine, delivered SC alongside pembrolizumab, significantly reduced recurrence risk by 49% and increased 2.5‑year recurrence-free survival from ~56% to ~75%. Early NSCLC studies of the same platform show encouraging safety and immune activation

The SC route is also enhancing cellular immunotherapies. Studies in renal cell carcinoma have shown that subcutaneous IL‑2, when used post-surgery or with CAR-T/TIL therapy, achieves ~17–20% response rates, including complete responses in ~3% of patients, with improved tolerability vs. IV high-dose regimens

Subcutaneous delivery is further being tested as an adjunct to checkpoint blockade. In melanoma and RCC, trials combining SC cytokines or TLR agonist adjuvants with anti‑PD‑1 demonstrate enhanced T cell priming and reshaping of the tumor microenvironment (e.g., EVX‑01 plus anti‑PD‑1).

• Melanoma (KEYNOTE‑942): mRNA‑4157 SC + pembrolizumab reduced recurrence/mortality by 49% at 3 years.

• Resected RCC: SC IL‑2 in high‑risk patients yielded a 3‑year disease‑free survival of ~33% and overall survival of ~70%, with good tolerabilit.

Advantages and Limitations of Subcutaneous Immunotherapy in Cancer

Subcutaneous immunotherapy (SCIT) provides several key advantages that make it attractive for cancer treatment. Its ease of administration in outpatient settings improves patient comfort and adherence, especially compared to intravenous (IV) therapies. The lower systemic exposure associated with SC delivery helps reduce toxicity—particularly for cytokines like IL-2—making it a safer alternative to high-dose systemic infusions. Additionally, the slow-release kinetics at the injection site enhance antigen presentation over time, supporting stronger and more durable immune responses.

Despite these benefits, SCIT also presents some limitations. Local injection-site reactions such as swelling or redness are common. There are also formulation and dosing challenges, especially when delivering large or complex molecules. As a monotherapy, SCIT may show limited efficacy in “cold” tumors lacking baseline immune infiltration, often requiring combination with other immunotherapies. Importantly, SCIT is still in the early stages of oncology development, with most applications currently under investigation in clinical trials and not yet part of standard treatment protocol.