The crux of the problem lies in tumor biology. Roughly 92 to 98 percent of locally advanced rectal cancers are microsatellite stable, meaning their DNA mismatch repair machinery is intact. This is the opposite of the microsatellite instability-high profile that has made some colorectal cancers famously responsive to immunotherapy. In landmark trials such as KEYNOTE-016 and CheckMate-142, patients with proficient mismatch repair tumors showed almost no objective response to PD-1 blockade alone or even in combination with CTLA-4 blockade, while the deficient mismatch repair population achieved objective response rates of 30 to 70 percent with durable survival benefits. Microsatellite stable tumors are often described as immunological deserts, or cold tumors, because they lack the infiltrating immune cells and antigen visibility that checkpoint inhibitors exploit. Monotherapy immunotherapy, the review concludes, is simply insufficient to change this phenotype.

This is where radiotherapy enters the picture, and the mechanistic story is one of the most elegant in modern oncology. Radiation triggers immunogenic cell death in tumor cells, flooding the local environment with tumor-associated antigens while simultaneously upregulating major histocompatibility complex class I molecules on the tumor surface, which enhances antigen presentation to the immune system. Radiation also activates the cGAS-STING pathway: dying tumor cells release double-stranded and mitochondrial DNA into the cytoplasm, where the cGAS sensor detects it and triggers a signaling cascade through STING, TBK1, and IRF-3 that produces type I interferons. These interferons mature dendritic cells, which in turn prime tumor-specific T lymphocytes, amplifying the adaptive antitumor response. Crucially, the same interferons upregulate PD-L1 on tumor cells, creating precisely the molecular target that checkpoint inhibitors are designed to attack.

The synergy runs in both directions. Radiation-induced PD-L1 expression is not merely a target but a mechanism of resistance: high PD-L1 accelerates DNA double-strand break repair through non-homologous end joining, shielding tumor cells from radiation damage. Blocking the PD-1/PD-L1 pathway restores radiosensitivity. Immunotherapy also improves tumor oxygenation, because activated CD8-positive T cells produce interferon-gamma that normalizes tumor vasculature, increasing blood perfusion. Since molecular oxygen is what fixes radiation-induced free radical damage into irreversible lethal lesions, better oxygen supply means better radiation kill. Radiation, meanwhile, acts as an in situ vaccine, generating neoantigens from radiation-induced mutations that tumor-specific T cells can recognize, effectively converting the irradiated tumor into a source of personalized immunotherapy targets. The combined effect, the authors argue, epitomizes the concept of one plus one exceeding two.

The clinical evidence is accumulating at remarkable speed, particularly for short-course radiotherapy regimens. In the Averectal study, a multicenter phase II trial, patients received 25 Gy in five fractions followed by six cycles of mFOLFOX-6 plus avelumab before surgery; 37.5 percent achieved a pathological complete response and 67.5 percent a major pathological response, with three-year disease-free survival of 85 percent. The randomized phase III UNION trial compared short-course radiotherapy followed by CAPOX chemotherapy and camrelizumab against long-course chemoradiotherapy followed by CAPOX alone, and found pathological complete response rates of 39.8 percent versus 15.3 percent, a highly significant difference with no new safety signals. The TORCH trial reported complete response rates above 54 percent with short-course radiotherapy, CAPOX, and toripalimab in microsatellite stable patients, while SPRING-01 showed that adding sintilimab raised the pathological complete response rate from 32.7 to 59.2 percent without increasing grade 3 to 4 toxicity. STELLAR II confirmed the pattern, with complete response rates of 45.5 percent versus 25.0 percent when a PD-1 inhibitor was added.

Long-course radiotherapy strategies have produced equally compelling results through a different logic: administering radiation, chemotherapy, and immunotherapy synchronously to exploit the window when radiation is actively releasing antigens and recruiting immune cells. The AVANA study, the first phase II trial targeting microsatellite stable patients with this approach, achieved a 23 percent pathological complete response rate with avelumab added to standard chemoradiotherapy. The NECTAR study reached 40 percent with tislelizumab, and a randomized trial from Sun Yat-sen University Cancer Center showed complete response rates of 44.8 percent versus 26.9 percent when sintilimab was added. Japan’s VOLTAGE-A trial, the first to evaluate long-course chemoradiotherapy followed by nivolumab, doubled the historical pathological complete response rate to 30 percent in microsatellite stable patients, and three-year follow-up confirmed improved disease-free survival. The European PANDORA trial achieved a 34.5 percent pathological complete response rate with durvalumab after chemoradiotherapy, with 81.8 percent of patients achieving major pathological response, opening the door to organ-preserving watch-and-wait management for some.

That organ preservation goal may prove to be the most transformative aspect of this research program. The PKUCH-04 study from Peking University Cancer Hospital pioneered a three-phase design of induction immunotherapy and chemotherapy, concurrent chemoradiotherapy, and consolidation chemotherapy in high-risk patients, achieving a clinical complete response rate of 48 percent, high enough that some patients could safely forgo surgery altogether. The OPRA trial had already shown three-year organ preservation rates of 40 to 50 percent with total neoadjuvant therapy alone, and the review suggests immunotherapy may push this higher. However, the authors caution that watch-and-wait is not a nonoperative cure: local regrowth is not uncommon, most often within two years, and salvage surgery in a previously irradiated field is technically demanding. Standardized criteria for assessing clinical complete response remain lacking, and success depends on rigorous follow-up and patient compliance.

Significant questions remain before radioimmunotherapy can become standard care. No consensus exists on whether short-course or long-course radiotherapy should anchor the combination, and the review stresses that choice should be individualized based on tumor burden, margin status, and organ preservation goals, with head-to-head phase III trials now being planned. Predictive biomarkers are another frontier: circulating tumor DNA shows extraordinary promise, with the UNION study reporting an area under the curve of 0.983 for distinguishing pathological complete responders, and T cell receptor clonality, PD-L1 expression, tumor-infiltrating lymphocyte density, specific gene mutations, and even gut microbiome composition are emerging as potential selection tools. Safety also demands attention, since both radiation and checkpoint inhibitors cause gastrointestinal toxicity, and clinicians must distinguish radiation proctitis from immune-related colitis, which require entirely different management.

Looking further ahead, the review outlines an ambitious pipeline. Dual immunotherapy adding CTLA-4, LAG-3, or TIGIT blockade is under investigation, with the NEOCART trial of the bispecific antibody cadonilimab reporting a 37 percent pathological complete response rate. Anti-angiogenic combinations are gaining traction, with the Dutch TARZAN study achieving a 45 percent clinical complete response rate using bevacizumab and atezolizumab after short-course radiotherapy. Emerging radiation technologies may reshape the field entirely: FLASH radiotherapy, delivered at ultra-high dose rates above 100 Gy per second, could spare normal tissue and preserve circulating immune cells, theoretically creating ideal conditions for combination therapy, while node-sparing irradiation strategies aim to protect immune function by limiting target volumes. With artificial intelligence and multi-omics modeling promising individualized treatment predictions, the authors conclude that although the field is still in its infancy, the convergence of radiotherapy and immunotherapy is poised to rewrite treatment guidelines and bring genuinely personalized, potentially surgery-free care to patients with the most common form of rectal cancer.

Subject of Research: Combining radiotherapy with immune checkpoint inhibitors to treat microsatellite stable locally advanced rectal cancer

Article Title: Review of radiotherapy combined with immune checkpoint inhibitors for microsatellite stable locally advanced rectal cancer

Article References: Pan, X., Niu, S., Wen, J., Bao, Y., & Li, J. (2026). Review of radiotherapy combined with immune checkpoint inhibitors for microsatellite stable locally advanced rectal cancer. Holistic Integrative Oncology, 5(1), Article 29. https://doi.org/10.1007/s44178-026-00249-w

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00249-w

Keywords: rectal cancer, radiotherapy, immunotherapy, immune checkpoint inhibitors, microsatellite stable, colorectal cancer, neoadjuvant therapy, organ preservation, PD-1 inhibitors, tumor microenvironment, pathological complete response, cGAS-STING pathway