Sarcomas are cancers derived from mesenchymal tissue and account for approximately 1% of adult malignancies, based on the 2020 prevalence estimates for the United States.1,2 The classical primary division of these tumors is between soft tissue sarcomas (STS), which comprise 73% of sarcomas by prevalence (77% by incidence), and bone sarcomas comprising the other 27% of sarcomas by prevalence (23% by incidence), based on the 2020 prevalence estimates for the United States.1,3 It was estimated that there would be 13,400 new cases of STS, and 5,140 deaths due to STS for the United States in 2023.4 The incredible diversity of STS has made them difficult to study. By most estimates, there are over 50 different histological subtypes of STS. While some of these are variations of similar clinical entities, many STS subtypes represent truly distinct diseases with completely unique biology, clinical behaviors, and responses to treatment.5 While liposarcoma, leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS) subtypes together comprise over half of STS with each affecting >2,000 new patients annually, some STS subtypes are truly ultra-rare.6 The rarity of many subtypes means that clear therapeutic advances need to be observed in relatively small sample sizes. Conducting randomized studies in this disease, which varies biologically based on individual subtypes, is quite challenging. Despite these difficulties, there have been a number of drug approvals in recent years. Some of these have been for relatively common subtypes such as trabectedin (liposarcoma and leiomyosarcoma) and eribulin (liposarcoma), but others have been for relatively rare histologies such as nab-sirolimus for perivascular epithelioid cell tumor (PEComa) and tazemetastat for epithelioid sarcoma.7, 8, 9, 10 Yet overall, outcomes for advanced (unresectable and metastatic) STS remain poor with a median overall survival of 22 months, based on follow-up data from recent randomized studies.11,12

Radiotherapy (RT) has been an integral and standard part of treatment of STS for decades.13 This is particularly true in localized STS of the extremity, where in one study with 20-year follow-up of extremity STS, patients treated with limb salvage surgery were randomized to adjuvant external beam radiotherapy (EBRT) versus no adjuvant EBRT, and the EBRT arm had improved 10- and 20-year overall survival, 82% versus 77% and 71% vs 64%, but these differences were not statistically significant.14 In the localized setting, both adjuvant and neoadjuvant strategies are frequently utilized, and currently, hypofractionated schedules are being increasingly explored.15,16

Radiotherapy also plays a critical role in the metastatic setting, both in the treatment of oligometastatic disease and in the palliation of painful lesions. Stereotactic ablative radiotherapy (SABR), also known as stereotactic body radiotherapy (SBRT),17 in particular has been highly effective for oligometastatic pulmonary metastasis and the local control of spinal disease.18,19 SABR involves image guidance (hence “stereotactic”) to achieve precise and accurate delivery of highly conformal, high dose (hence “ablative”) radiotherapy to limited-volume targets in the body outside of the cranium17 in oligo-fractions, which is defined as five or fewer fractions.20,21 Stereotactic radiosurgery (SRS) is like SABR except SRS is used to treat targets in the cranium,17 so SRS can be a desirable treatment option for brain metastases.22 Proton beam radiotherapy may be useful in select cases, as it may allow for a reduction of the radiotherapy dose to normal tissues surrounding a malignant tumor, potentially allowing for increased dose to the malignant tumor.23,24

Immunotherapy offers the potential to move beyond many traditional therapies with the potential for durable disease regression and elimination with relatively few toxicities compared with conventional cytotoxic chemotherapy. However, while activity is clear for some subtypes such as alveolar soft part sarcoma (ASPS) and UPS, clinical results for immunotherapy remain suboptimal generally for STS, and are completely absent in certain STS subtypes, raising the importance of clinical trials to optimize immunotherapy efficacy.25, 26, 27

There is a long history of using radiotherapy to potentiate immunotherapy in a wide variety of cancers and there is a growing movement towards evaluating the combination of radiotherapy and immunotherapy in STS.28,29 In this review, we will discuss the rationale and outline some of the prominent efforts to combine radiotherapy and immunotherapy in STS for enhanced therapeutic efficacy.30