Over the past decade, immunotherapy has become a cornerstone in treating various malignancies. Chimeric antigen receptor (CAR) T-cells and immune checkpoint inhibitors (ICI) have shifted the treatment paradigm for leukemia, lymphoma, lung cancer, melanoma,1, 2, 3, 4 and many other cancers. Despite these revolutionary advances, most cancer patients will not benefit from immunotherapy and additional progress is needed. The effectiveness of CAR T-cells remains limited in treating solid tumors, and ICI are less successful at generating clinically meaningful anticancer responses as monotherapy in solid tumors with low mutational burdens, such as soft tissue sarcomas (STS).5,6 Therefore, it is important to explore other therapies that can work synergistically with immunotherapy to induce a robust anticancer response in other histologies.

Radiotherapy has long been proposed to have the potential to work synergistically with immunotherapy to enhance antitumor response in primary tumors and promote a systemic antitumor immune response. There are numerous immune modulating mechanisms of radiotherapy, some enhancing antitumor effects and some promoting immunosuppression.7 In-situ vaccination has been a mechanism of particular interest, in that it could generate synergy with ICI. The induction of immunogenic cell death increasing the availability and presentation of tumor antigens coupled with increased trafficking of lymphocytes into the tumor micro-environment (TME) could induce new and expand existing antitumor immune responses. Clinical evidence supports this concept in that on rare occasions, an abscopal effect of radiotherapy has been reported where a systemic antitumor effect is observed outside the radiation field.8, 9, 10, 11 In these rare instances, it is likely that radiotherapy depends, in part, on this in-situ vaccination effect for its efficacy. However, the rarity of abscopal events suggests that radiotherapy generally does not generate a sufficient in-situ vaccination effect strong enough to eradicate systemic disease. As with other vaccine approaches, it is likely that vaccine adjuvants will be required to realize the full capacity of radiotherapy induced in-situ vaccination. This may be of particular relevance in diseases such as STS where the antitumor T cell response is rarely strong enough to generate clinical response from ICI monotherapy.

Toll-like receptor (TLR) agonists and other immunotherapies such as Fms-like tyrosine kinase 3 ligand (FLT3L), stimulator of interferon genes (STING) agonists, CD40 agonists, oncolytic viruses, and cytokines have shown promising antitumor effects in preclinical and clinical studies. Local injection of these immunostimulants in STS with radiotherapy could produce a robust in-situ vaccination effect and allow potent activation of both innate and adaptive immune systems while minimizing side effects that are commonly associated with systemic therapies.

The objective of this review is to explore the antitumoral effectiveness of combining intratumoral injection of TLR agonists or other immunostimulants into STS with adjuvant radiotherapy to generate local and systemic antitumor immune responses. We will examine both preclinical and clinical trial data to provide a comprehensive overview of the potential and limitations of such therapeutic strategies. The ultimate goal is to shed light on the scientific rationale and the clinical feasibility of integrating locally administered immunostimulants with radiotherapy for the treatment of STS.