This study provides a novel immuno-combined chemotherapy strategy for the treatment of MSS/pMMR locally advanced rectal cancer, suggesting that the synergistic activation of anti-tumor immunity by PD-1 and IL-2 may overcome the ‘cold tumor’ microenvironment, offering important insights for research on immunotherapy-resistant solid tumors.
Literature Overview
The article “Total neoadjuvant chemotherapy combined with PD‑1 blockade and IL‑2 in MSS/pMMR locally advanced rectal cancer: short-term results of a prospective, single-arm phase II study,” published in the journal Signal Transduction and Targeted Therapy, systematically investigates the efficacy and safety of total neoadjuvant chemotherapy (TNT) combined with the PD-1 inhibitor sintilimab and interleukin-2 (IL-2) in patients with microsatellite stable (MSS) or proficient mismatch repair (pMMR) locally advanced rectal cancer (LARC). The study demonstrates a remarkably high pathological complete response (pCR) rate of 42.4% without the use of radiotherapy, with manageable safety. These findings offer a new perspective for treating traditionally ‘cold’ colorectal tumors and hold significant potential for clinical translation.Background Knowledge
Treatment of locally advanced rectal cancer (LARC) has long relied on preoperative chemoradiotherapy to reduce the risk of local recurrence. However, the long-term toxicities associated with radiotherapy—such as intestinal fibrosis, anastomotic leakage, and sexual dysfunction—limit its applicability. In particular, MSS/pMMR tumors, which lack high tumor mutational burden (TMB) and immune cell infiltration, are considered ‘cold tumors’ and are unresponsive to single-agent PD-1 immunotherapy. Although chemoradiotherapy can enhance immunogenicity, combining it with immune checkpoint inhibitors (ICIs) remains constrained by overlapping toxicities. Therefore, a key challenge in current research is to convert ‘cold’ tumors into ‘hot’ tumors without relying on radiotherapy. This study leverages IL-2, a classical immune agonist, to synergize with PD-1 blockade by activating CD8+ T cells and natural killer (NK) cells, thereby reshaping the tumor microenvironment (TME) and enhancing the combined effects of chemotherapy and immunotherapy. This strategy bypasses radiotherapy dependence and offers a potential curative, radiotherapy-free pathway for patients with MSS/pMMR LARC.
Research Methods and Experiments
The study employed a single-arm, open-label phase II design, enrolling 33 patients with MRI-confirmed MSS/pMMR LARC who received six cycles of CapOX (capecitabine + oxaliplatin) combined with sintilimab (a PD-1 antibody) and IL-2 as total neoadjuvant therapy. Each cycle spanned three weeks, with IL-2 administered subcutaneously at 1 million IU every other day to maintain immune activation. All patients underwent radical surgery after treatment, with the primary endpoint being the pCR rate. Surgery timing was evaluated by a multidisciplinary team (MDT), and blood and tissue samples were collected for immunophenotyping. Key experiments included flow cytometry to monitor dynamic changes in peripheral blood immune cell subsets and multiplex immunofluorescence staining to analyze immune cell infiltration within the tumor microenvironment, thereby validating the synergistic mechanism of IL-2 and PD-1 in T-cell activation.Key Conclusions and Perspectives
Research Significance and Prospects
This study challenges the traditional notion that MSS/pMMR rectal cancer is unresponsive to immunotherapy. By leveraging the synergistic effects of PD-1 and IL-2, it achieves a high pCR rate and provides high-quality evidence for radiotherapy-free neoadjuvant strategies. Future studies should include randomized controlled trials in broader populations and integrate liquid biopsy or single-cell sequencing to dynamically monitor TME changes, optimizing treatment duration and patient selection.
From a drug development perspective, this study supports the reevaluation of IL-2 in solid tumor immunotherapy, particularly its potential in combination with PD-1 inhibitors. Although high-dose IL-2 has been limited by toxicity, the moderate-to-low dose regimen used here showed favorable tolerability, highlighting dose optimization as a key factor. Future efforts may focus on developing long-acting or targeted IL-2 variants (e.g., IL-2v) to enhance efficacy while minimizing toxicity.
In terms of clinical monitoring, the discordance between pCR and clinical complete response (cCR) suggests that current imaging criteria may underestimate pathological responses. Combining multimodal imaging with dynamic monitoring of circulating tumor DNA (ctDNA) may more accurately identify complete responders, thereby supporting “watch-and-wait” strategies and avoiding unnecessary surgeries.
Conclusion
This study represents a groundbreaking advance in the treatment of MSS/pMMR locally advanced rectal cancer. By combining total neoadjuvant chemotherapy with PD-1 blockade and IL-2, it achieves a 42.4% pathological complete response rate without radiotherapy, significantly reducing the risk of long-term toxicity. This strategy not only overcomes the resistance of ‘cold tumors’ to immunotherapy but also reshapes the tumor immune microenvironment through activation of CD8+ T cells and NK cells. The findings provide high-quality phase II evidence for a radiotherapy-free approach in rectal cancer, potentially reshaping current treatment paradigms. Future validation in phase III randomized trials is needed to assess long-term impacts on disease-free and overall survival. Moreover, the success of this regimen offers a replicable immune-activation pathway for other immunologically ‘cold’ solid tumors, underscoring the resurgence potential of IL-2 in modern immunotherapy. Bridging fundamental immune mechanisms with translational applications, this study lays the foundation for expanding precision immunotherapy in colorectal cancer.
