By: Jeff Martin – Jeff is the Founder and Principal Consultant at Oncoleader, LLC, a Strategic Scientific Communications consulting firm specializing in immuno-oncology.

The landscape of cancer treatment seems to be on the brink of a significant shift, with the future of immunotherapy poised to leverage the innate immune system. Traditionally, the focus has been on enhancing the adaptive immune response, with a particular interest in therapeutic strategies that harness the anti-tumor power of T cells.

However, as more technologies are developed, more patients are treated, and more clinical data is becoming available, the limitations of strictly T cell-centered approaches are becoming increasingly apparent.

The “Problem” with Current Immunotherapies

Most immunotherapies in clinical use today aim to boost some aspect of the adaptive immune system. While these therapies have transformed cancer treatment, their efficacy is often limited by the need for support from the innate immune system. The adaptive immune response cannot function in isolation; it relies on the innate immune system to initiate and sustain its activities.

Tumors with dysfunctional innate immunity often exhibit a compromised adaptive immune profile. These "cold" tumors, characterized by low levels of infiltrating lymphocytes, are notoriously resistant to conventional immunotherapies. This resistance highlights the need for a paradigm shift in cancer treatment strategies.

A New Approach: Stimulating the Innate Immune System

Therapeutically stimulating the innate immune system offers a promising strategy to enhance the efficacy of adaptive immune-centered therapies. But how can we effectively stimulate intratumoral innate immunity?

Here are three main strategies that cancer biologists are exploring:

·         Activating the cGAS/STING Pathway: This pathway is crucial for producing immune-stimulating interferons in response to cytoplasmic DNA, which signals potential viral infection. By activating this pathway, we can recruit and stimulate immune cells, such as dendritic cells and T cells, to the tumor site, enhancing the overall immune response.

·         Toll-like Receptor (TLR) Agonism: TLRs are ancient components of the innate immune system that recognize molecular patterns on microbes and damaged cells. By therapeutically stimulating TLRs, we can trigger an inflammatory response that recruits and activates immune cells to combat the growth tumor and enhance the overall anti-tumor immune response.

·         Innate Immune Cell Checkpoint Inhibitors: Just as tumors can inhibit T cells with immune checkpoints (the most therapeutically relevant immune checkpoint is the PD-1/PD-L1 interaction), they can also suppress innate cells like macrophages and natural killer cells using similar mechanisms. Antibodies that block these inhibitory interactions can unleash innate cell activity, bolstering intratumoral immunity.

Below I’ve included a list (non-comprehensive) of the various companies pursuing these strategies.

The Future is Combination Immunotherapy

The future of cancer treatment lies in combination immunotherapy, which integrates cell therapy with other forms of immunostimulatory therapeutics. By focusing on innate-centered therapies, we can develop more effective and personalized treatments that overcome the limitations of current approaches.

As we continue to explore these strategies, the potential for innate immune system-targeted therapies to play a prominent role in cancer therapy becomes increasingly clear. Keep an eye on these developments, as they represent the next frontier in the fight against cancer.