3644 Background: In patients with proficient mismatch repair (pMMR) locally advanced rectal cancer (LARC), the integration of PD-1 inhibitor into total neoadjuvant chemoradiotherapy (iTNT) has demonstrated promising potential to enhance complete response (CR) rates and facilitate organ preservation. However, the combined use of radiotherapy and surgical intervention frequently leads to increased functional impairment relative to either modality administered independently. Concurrently, the combination of chemotherapy and PD-1 inhibitor has been shown to promote tumor downstaging, thereby enabling sphincter-preserving surgery while mitigating radiation-induced injury. This trial evaluates oncological efficacy and functional outcomes of two iTNT regimens: CAPOX plus PD-1 inhibitor with or without SCRT in neoadjuvant treatment of pMMR LARC patients. Methods: The TORCH-iTNT trial (NCT06281405) is a prospective, multicenter, randomized phase II study involving 192 patients with pMMR LARC (T3-4/N+M0). Participants were randomized into Group A (6 cycles of CAPOX plus toripalimab) or Group B (SCRT [25Gy/5Fx] followed by 6 cycles of CAPOX plus toripalimab). Patients achieving clinical complete response (cCR) were offered a watch-and-wait (W&W) strategy, while those without cCR were advised to undergo surgery. Group A patients with positive circumferential margins received adjuvant chemoradiotherapy. The primary endpoint was CR rate (pathological complete response [pCR] plus cCR). Secondary endpoints included organ preservation rate, anorectal function, adverse effects, and survival outcomes. Results: By December 31, 2025, 192 patients were enrolled, with 137 completing treatment (Group A: 65; Group B: 72). Baseline characteristics were balanced, with 97.1% (133/137) exhibiting at least one high-risk feature: lower tumor location (≤5cm), cT4, cN2, MRF+, or EMVI+. In Group A, 5 patients achieved cCR and adopted W&W, compared to 22 in Group B. Of the 54 and 49 patients in Group A and B who underwent surgery, pCR was observed in 19 (35.2%) and 22 (44.9%) cases, respectively. Five non-cCR patients in Group A declined surgery or were still undergoing treatment. Disease progression occurred in one patient per group. The overall CR rates were 36.9% (24/65) in Group A and 61.1% (44/72) in Group B. The most frequent grade 3-4 toxicity was thrombocytopenia (Group A: 12.3%; Group B: 12.5%). Conclusions: This study is the first comparative analysis of two iTNT regimens in LARC. Unprecedentedly, neoadjuvant CAPOX plus PD-1 inhibitor achieved a promising CR rate in pMMR LARC, and this CR rate can be further enhanced with the addition of SCRT prior to immunochemotherapy. Further follow-up is necessary to assess long-term efficacy and functional endpoints. Clinical trial information: NCT06281405 .

3578 Background: Microsatellite-stable (MSS) tumors comprise ~95% of metastatic colorectal cancer cases and exhibit intrinsic resistance to immunotherapy. Emerging evidence suggests systemic therapy may enhance immunotherapy responsiveness, while radiotherapy could improve efficacy by overcoming resistance and reducing tumor burden. The MIRACLE-2 study evaluated the safety and efficacy of combining radiotherapy with systemic therapy and tislelizumab as first-line treatment for unresectable metastatic MSS rectal cancer (RC). Methods: MIRACLE-2 was a prospective, single-arm, phase II study. Inclusion criteria: MSS RC with primary tumor ≤10 cm from anal verge on MRI and synchronous unresectable metastases. Patients received hypofractionated radiotherapy (HFRT) for primary lesions and HFRT or SBRT for metastases, followed by systemic therapy: FOLFOX-bevacizumab-tislelizumab for RAS/BRAF-mutant patients or FOLFIRI-cetuximab-tislelizumab for wild-type patients. Reassessment every 8 weeks. Patients achieving resectable disease underwent primary tumor resection and metastasectomy/local ablative therapies for metastases. For patients unable to preserve anal sphincter, a watch-and-wait (WW) strategy was considered if clinical complete response (cCR) of primary tumor was achieved. Otherwise, systemic therapy continued until progression/intolerable toxicity. Primary endpoint: ETS rate (≥20% target lesion reduction at 8 weeks post systemic therapy initiation). Secondary endpoints: disease control rate (DCR), duration of response (DOR), overall survival (OS), progression-free survival (PFS), and safety. Results: As of December 31, 2025, efficacy data were available for 50 patients (38 males, 76.0%; median age 57 years, range 30-73). Among these, 52.0% had liver metastases, 8.0% lung metastases, and 40.0% both liver and lung metastases. RAS/BRAF mutations were detected in 56.0% of primary tumors. Median treatment courses: eight (range 3-12). Overall, 18% (9/50) attained no evidence of disease (NED). ETS rate: 76.0%; DCR: 88.0%. Median follow-up: 19.9 months (95% CI: 16.4-23.4). Among 34 patients with complete/partial response, median DOR: 8.0 months (95% CI: 5.2–10.8), with 1-year DOR rate of 20%. Median PFS: 9.3 months (95% CI: 7.1-11.5), with 1-year PFS rate of 33.4%. Median OS: 23.2 months (95% CI: 15.1-31.3), and 1-year OS rate: 93.3%. No grade 5 treatment-related adverse events (TRAEs) occurred. All-grade TRAEs: lymphopenia (95.9%), anemia (91.8%), and leukopenia (69.4%). Grade 3/4 TRAEs: lymphopenia (36.7%), neutropenia (26.5%), and leukopenia (20.4%). Conclusions: The combination of radiotherapy, systemic therapy, and tislelizumab showed a high ETS rate and manageable safety profile in first-line unresectable MSS RC. Long-term outcomes require further follow-up. Clinical trial information: NCT05359406 .

Tumor-associated macrophages (TAMs) pose a significant obstacle to successful cancer immunotherapy in colorectal cancer (CRC). Herein, we demonstrate that genetic deletion of PGE2 receptors EP2/EP4 markedly sensitizes CRC tumors to anti-PD-1 therapy. We then report the development of TP-18, a potent and orally available dual EP2/EP4 antagonist. TP-18 treatment effectively depletes a highly immunosuppressive VSIG4high TAM subset and enhances cytotoxic CD8+ T cell-mediated CRC tumor elimination. Mechanistically, TP-18 dampens the expression of VSIG4 by blunting EP2/EP4-Gαs-PKA signaling. Notably, VSIG4high TAMs from CRC-tumor-bearing mice display robust immunosuppressive features, and similar VSIG4high populations are also detected in patients with CRC and other cancers. Importantly, TP-18 improves the therapeutic efficacy of anti-PD-1 therapy in CRC mouse models and in patient-derived tumor immune organoids. Collectively, our findings establish targeting of EP2/EP4-driven expansion of VSIG4high TAMs as a promising therapeutic strategy to overcome immunotherapy resistance.

The clinical benefit of extending tumor treating fields (TTFields) beyond concurrent chemoradiotherapy (CRT) for newly diagnosed glioblastoma (ndGBM) is unclear. This multi-institutional retrospective study compared patients who continued TTFields into adjuvant temozolomide (CRT-TT, n = 68) versus those who discontinued after CRT (CRT-T, n = 32). With a median follow-up of 36.9 months, median progression-free survival (mPFS) did not significantly differ between the groups (12.8 vs. 12.5 months; hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.57-1.59; p = 0.853) nor did median overall survival (mOS) (20.6 vs. 16.6 months; HR 0.73, 95% CI 0.43-1.27; p = 0.267). Additionally, continuing TTFields into the adjuvant phase did not increase scalp toxicity. Although a numerically longer OS was seen in the CRT-TT group, the lack of statistical significance may reflect limited power and non-randomized allocation. These findings underscore the need for further investigation.

3599 Background: Immunotherapy-based total neoadjuvant therapy (iTNT) is a promising strategy to enhance complete response rates and facilitate organ preservation in locally advanced rectal cancer (LARC). However, it is linked to a considerable incidence of severe hematotoxicity, while reliable predictive biomarkers are lacking. Body composition, reflecting nutritional status, has been linked to treatment-related toxicity, but its relationship with iTNT toxicity remains unclear. This study aimed to investigate the association between body composition and hematotoxicity of iTNT and to develop a predictive model. Methods: A cohort of 204 LARC patients treated with iTNT was included for model development, with internal training and validation via five-fold cross-validation. Additionally, 43 metastatic rectal cancer patients treated with the same regimen served as the external validation cohort. Body composition parameters were obtained from pretreatment CT images at L3. LASSO regression was applied to select variables and four machine learning (ML) algorithms including logistic regression, random forest (RF), support vector machine (SVM), and extreme gradient boosting (XGBoost) were developed. Results: 33.8% of the discovery cohort experienced grade 3-4 hematotoxicity. Among baseline characteristics, skeletal muscle index (SMI) showed the most significant correlation with toxicity. The cut-offs for SMI, determined by optimal stratification, were 50.0 cm²/m² for males and 39.6 cm²/m² for females. Patients with low SMI had a higher incidence of severe toxicities ( P < 0.001). Seven features were included in the ML models: age, body mass index (BMI), SMI, subcutaneous adipose tissue index (SATI), subcutaneous adipose tissue attenuation (SAT_HU), visceral adipose tissue index (VATI), and skeletal muscle attenuation (SM_HU). The predictive performance of the models is summarized in the following table. Overall, the SVM model showed the highest discriminative performance and robust generalizability. Conclusions: SMI was significantly associated with hematotoxicity during iTNT. A CT-based machine learning model was developed and validated to predict hematotoxicity, with the SVM model showing the most robust performance (AUC > 0.85) to guide clinical decision-making. Cohort Model Accuracy Sensitivity Specificity AUC Internal validation SVM 0.850 ± 0.024 0.849 ± 0.021 0.833 ± 0.027 0.881 ± 0.019 RF 0.755 ± 0.037 0.749 ± 0.037 0.777 ± 0.032 0.803 ± 0.033 Logistic regression 0.704 ± 0.048 0.672 ± 0.055 0.720 ± 0.048 0.730 ± 0.033 XGBoost 0.796 ± 0.024 0.769 ± 0.038 0.788 ± 0.036 0.814 ± 0.027 External validation SVM 0.821 ± 0.034 0.829 ± 0.026 0.800 ± 0.019 0.858 ± 0.029 RF 0.713 ± 0.030 0.723 ± 0.051 0.734 ± 0.043 0.750 ± 0.038 Logistic regression 0.666 ± 0.034 0.652 ± 0.044 0.649 ± 0.027 0.671 ± 0.037 XGBoost 0.751 ± 0.046 0.714 ± 0.038 0.744 ± 0.031 0.779 ± 0.044

3634 Background: The prognosis for locally advanced colon cancer (LACC) with bulky nodal disease and/or clinically T4 stage remains poor, with high rates of recurrence and metastasis. Immunotherapy has become the standard treatment for deficient mismatch repair or microsatellite instability-high (dMMR/MSI-H) colon cancer. However, there has been little progress for the majority of cases, which was mismatch-repair proficient or microsatellite stable (pMMR/MSS). For locally advanced colon cancer with T4b stage or bulky lymph nodes, neoadjuvant chemotherapy is currently widely used. Whether combining it with immunotherapy and radiotherapy can improve efficacy is worthy of exploration. TORCH-C is the first study to evaluate this combination. Methods: TORCH-C is a prospective, multicenter, randomized phase 2 study that enrolled patients from April 3, 2023, through September 9, 2025. A total of 120 high-risk LACC (T4/bulky N+M0，pMMR/MSS) patients were 1:1 randomized to either an immunotherapy combined with SCRT and CAPOX chemotherapy group (group A) or a chemotherapy alone group (group B). Patients in the group B received 4 cycles of CAPOX (oxaliplatin 130 mg/m 2 intravenously day 1 and capecitabine 1000 mg/m 2 orally days 1-14). Patients in the group A received SCRT (25Gy in 5 fraction) and 4 cycles of the PD-1 inhibitor (serplulimab, 300mg intravenously day 1) combined with CAPOX. The radiotherapy target volume includes only the primary colon tumor and enlarged lymph nodes, without elective nodal irradiation. After neoadjuvant therapy, patients will be evaluated for radical colon resection. All patients will receive adjuvant chemotherapy of four cycles of CAPOX. The primary outcome was pathological complete response (pCR) rate. The secondary outcomes included tumor downstaging, R0 resection, 3-year disease free survival (DFS), 3-year overall survival (OS), 3-year local recurrence-free survival and treatment-related toxicity. Results: 120 patients have been enrolled and randomized. 107 patients were included in the mITT analysis (54 in group A and 53 in group B). 103 have received surgery (50 in the chemotherapy group, 53 in the radiotherapy group). The pCR rate was 10% (5/50) in chemotherapy group (group B) and 45.3% (24/53) in the radiotherapy group (group A) ( P <0.05). The most common grade 3-4 adverse event (AE) among patients was thrombocytopenia, (22.2%, 12/54) in the group A and (18.9%, 10/53) in the group B. Conclusions: The combination of PD-1 inhibitor, SCRT, and chemotherapy shows promising efficacy and significantly improved pCR rates in patients with MSS/pMMR high-risk LACC. This regimen may provide a new therapeutic option to achieve R0 resection and improve long-term survival. Clinical trial information: NCT05732493 .

e15555 Background: Microsatellite-stable (MSS) tumors comprise ~95% of metastatic colorectal cancer cases and show low response to immunotherapy. Emerging evidence suggests combining radiotherapy with chemotherapy and PD-1 inhibitors may yield promising responses in locally advanced rectal cancer (RC). The MIRACLE-1 study evaluated this combination as upfront treatment for MSS RC with synchronous resectable metastases. Methods: MIRACLE-1 was a prospective, single-arm, phase II study. Inclusion criteria included MSS RC with primary tumor ≤10 cm from anal verge on MRI and limited liver/lung metastases deemed resectable. Patients received upfront radiotherapy: hypofractionated radiotherapy (HFRT) for primary lesion and HFRT or stereotactic body radiotherapy (SBRT) for metastases. Subsequently, six cycles of CAPOX plus Tislelizumab were administered. Tumor response was assessed after the third and sixth cycles. Further management included primary tumor resection and metastasectomy/local ablative therapies for metastases. For patients unable to preserve anal sphincter, a watch-and-wait (WW) strategy was considered if clinical complete response (cCR) of primary tumor was achieved. For patients achieving no evidence of disease (NED), adjuvant Tislelizumab was continued for up to 1 year postoperatively. Other patients received investigator-determined subsequent therapy. Primary endpoint: 1-year NED rate. Secondary endpoints: objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and safety. Results: As of December 31, 2025, efficacy data were available for 50 patients (37 males, 74.0%; median age 60 years, range 28-71). Among these, 62.0% had liver metastases, 20.0% lung metastases, and 18.0% both liver and lung metastases. RAS/BRAF mutations were detected in 62.0% of primary tumors. Upon reassessment, 38 patients (76.0%) achieved partial response (PR), 10 (20.0%) stable disease (SD), and 2 (4.0%) progressive disease (PD). ORR was 76.0%. Additionally, 54% (27/50) attained NED. Median follow-up duration was 18.7 months (95% CI: 15.5-21.9). Median PFS was 17 months (95% CI: 8.7-25.3), and 1-year PFS rate was 61.2%. Median OS was not reached, with 1-year OS rate of 83.5%. One treatment-related death occurred due to immunotherapy-induced hepatitis. All-grade treatment-related adverse events (TRAEs): thrombocytopenia (93.8%), lymphopenia (81.3%), and anemia (77.1%). Grade 3/4 TRAEs: thrombocytopenia (39.6%), lymphopenia (14.6%), and neutropenia (12.5%). Conclusions: In MSS RC patients with synchronous resectable metastases, radiotherapy combined with CAPOX plus Tislelizumab demonstrated promising antitumor efficacy and manageable safety profile. While initial findings are encouraging, longer follow-up is needed to assess durable outcomes. Clinical trial information: NCT05359393 .

Background Local excision (LE) has emerged as an organ-preserving option for patients with early rectal cancer, but high-risk pathological features significantly increase the risk of local recurrence. When completion total mesorectal excision (TME) is refused or medically unfeasible, combining radiotherapy, chemotherapy, and immunotherapy offers an adjuvant organ-preservation strategy in microsatellite-stable (MSS) rectal cancer. Objectives The TORCH-LE trial aims to evaluate the efficacy and safety of combining radiotherapy, chemotherapy, and immunotherapy as an adjuvant organ-preservation strategy for patients with high-risk pathological features after local excision (LE) who refuse or are unfit for completion TME. Design This is a prospective, multi-center, single-arm, hypothesis-generating phase II trial. Methods and Analysis A total of 60 patients with MSS early rectal cancer who have high-risk features following LE will be enrolled. All participants will receive short-course radiotherapy (SCRT; 25 Gy in 5 fractions), followed by four cycles of capecitabine and oxaliplatin (CapeOx) plus the PD-1 inhibitor toripalimab. The primary endpoint is the 3-year local recurrence-free survival (LRFS) rate, with an expected benchmark of 95% (target two-sided 95% CI: 85.6%–98.9%). Secondary endpoints include 3-year disease-free survival (DFS) rate, overall survival (OS) rate, treatment-related adverse events, and quality of life. Follow-up will include regular imaging and endoscopic surveillance. Discussion The TORCH-LE trial explores a novel adjuvant treatment strategy for early rectal cancer patients with high-risk features who are not eligible for or decline completion TME. By combining SCRT, chemotherapy, and immunotherapy, the study seeks to reduce recurrence risk while preserving rectal function. Given the single-arm design, findings should be considered exploratory and hypothesis-generating. The findings may support a more personalized organ-preserving approach and provide a rationale for future randomized trials.

147 Background: The prognosis for locally advanced colon cancer (LACC) with bulky nodal disease and/or clinically T4 stage remains poor, with high rate of recurrence and metastasis. Although neoadjuvant chemotherapy is recommended, tumor regression is often limited. Hypofractionated radiotherapy has demonstrated enhanced synergistic effects when combined with PD-1 inhibitors and chemotherapy in rectal cancer. TORCH-C is the first prospective study evaluating neoadjuvant short course radiotherapy (SCRT) combined with chemotherapy and a PD-1 inhibitor in patients with microsatellite stable or mismatch-repair proficient (MSS/pMMR) LACC. Methods: This is a prospective, multicenter, randomized phase II trial (NCT05732493). A total of 120 LACC (T4/bulky N+M0，pMMR/MSS) patients will be randomized to either a chemotherapy group or a radiotherapy group. The chemotherapy group receives 4 cycles of CAPOX. The radiotherapy group receives SCRT（25Gy in 5 fraction) and 4 cycles of the PD-1 inhibitor (serplulimab) combined with CAPOX. The radiotherapy target volume includes only the primary colon tumor and enlarged lymph nodes, without elective nodal irradiation. After neoadjuvant therapy, patients will be evaluated for radical colon resection. The primary endpoint is pathological complete response (pCR) rate. The secondary endpoints include tumor downstaging, R0 resection, 3-year disease free survival (DFS), 3-year overall survival (OS) , 3-year local recurrence-free survival and treatment-related toxicity. Results: As of August 31, 2025, 120 patients have been enrolled and randomized. Of these, 79 patients have completed neoadjuvant treatment and surgery (43 in the chemotherapy group, 36 in the radiotherapy group). All 79 patients achieved radical resection, with R0 resection rates of 95.3% (41/43) in the chemotherapy group (95.3%, 41/43), and 97.2% (35/36) in the radiotherapy group. The pCR rate (TRG 0) was 11.6% (5/43) in chemotherapy group and 47.2% (17/36) in the radiotherapy group. The most common grade 3-4 adverse event (AE) among patients completing neoadjuvant treatment was thrombocytopenia (15.3%, 15/98), including 5 cases of grade 4 thrombocytopenia. Conclusions: The combination of PD-1 inhibitor, SCRT, and chemotherapy shows promising efficacy and may significantly improve pCR rates in patients with MSS/pMMR high-risk LACC. This regimen may provide a new therapeutic option to achieve R0 resection and improve long-term survival. Clinical trial information: NCT05732493 .

Dose escalation in rectal radiotherapy shows promise for improving complete response rates and organ preservation, yet optimal expansion margins for rectal lesions remain unclear. This study aims to utilize high-resolution real-time imaging from MR-guided radiotherapy to characterize rectal motion uncertainties, optimize planning target volume (PTV) margins, and validate dosimetric outcomes, thereby enhancing the precision in rectal cancer dose escalation. A cohort of 22 advanced rectal cancer patients undergoing neoadjuvant radiotherapy on a 1.5T MR-Linac. Pre-treatment, intra-fraction, and post-treatment MR images were acquired for each fraction, with the rectum delineated according to the distance from the anus (upper, middle, lower). Inter- and intrafractional margins were determined by isotropic expansion of the segmented clinical target volume (CTV), with adequacy defined as covering 95

Characteristics of Patients Developing Tumor Recurrence

12039 Background: Colorectal cancer (CRC) patients often experience intestinal injury due to various treatment regimens, including chemotherapy (CT), chemoradiotherapy (CRT), and chemoradioimmunotherapy (ICRT). Despite advances in treatment, the underlying mechanisms of treatment-induced intestinal injury remain poorly understood. Methods: We performed single-cell RNA sequencing and histological staining on intestinal samples obtained from 18 colorectal cancer patients undergoing different treatment regimens, including untreated (CTRL), CT, CRT, and ICRT groups. We also employed bulk RNA sequencing to compare paired cancer and normal tissues from ICRT patients, identifying similarities and differences in gene expression patterns between the cancer and normal tissues. Results: Histological staining showed that there were no morphological changes in CT, while the damage in CRT was obvious, and the damage in ICRT was even more severe. Intestinal epithelial cells exhibit distinct differentiation trajectories into secretory and absorptive lineages. CRT-induced damage triggers reverse differentiation via revival stem cells (revSCs), driven by fetal-like genes like CLU, while ICRT disrupts this process. In CD8+T cells, effector T cells (TEFF) increase significantly in the ICRT group and differentially expressed genes (DEG) revealed unique patterns across different treatments, including upregulation of senescence-related genes in CRT and interferon- and TNF-related genes in ICRT, highlighting potential therapeutic targets for treatment-induced intestinal injury. In B cells, distinct differentiation pathways were observed, with CRT increasing atypical memory (Atm) B and ICRT promoting germinal center (GC) B, the latter correlating with follicular helper T (TFH) cells and potentially indicating tertiary lymphoid structure (TLS) formation, similar to the patterns of tumor response after ICRT. So we conducted bulk RNA sequencing analysis between paired tumor and normal tissues, which revealed a correlated expression of effector markers, suggesting a shared biological pattern between tissue damage and tumor killing. Also, patients in the ICRT group showed a significant correlation between clinical intestinal injury scores (LARS) and tumor regression grade (TRG), which means we can predict the treatment efficacy of ICRT by a more direct and convenient way. We also performed metabolism analysis and found tryptophan metabolism was significantly altered following CRT and ICRT treatments, closely linked to epithelial repair and inflammation, highlighting tryptophan metabolism can be used as treatment of intestinal injury. Conclusions: Our study presents a comprehensive single-cell atlas of treatment-induced intestinal injury in CRC patients, offering insights for future strategies to reduce treatment-related intestinal damage.

The efficacy of neoadjuvant radiotherapy (RT) in patients with rectal cancer (RC) is hindered by the plasticity and heterogeneity of cancer-associated fibroblasts (CAFs). However, the underlying mechanisms remain poorly understood. In this study, single-cell RNA sequencing of patients with RC samples revealed a CAF subpopulation characterized by high interferon (IFN) regulatory factor 1 (IRF1) expression. These IFN-licensed CAFs (ilCAFs) are enriched in tumors with enhanced RT responses across various solid tumors, including RC. Mechanistically, IFN gamma (IFN-γ) signaling drives the polarization of ilCAFs, leading to the recruitment of T cells and dendritic cells via CCL4/CCL5 secretion. Activation of IFN-γ/stimulator of IFN genes (STING) signaling reprograms the stroma and augments anti-tumor immunity in both RT-sensitive and RT-resistant colorectal cancer. Silencing STING in CAFs impairs ilCAF enrichment and diminishes tumor sensitivity to RT. Combining STING agonists with RT results in robust tumor control, providing a compelling rationale for clinical translation.

e15524 Background: MSS tumors account for 95% of metastatic colorectal cancer and are characterized by a low response rate to immunotherapy. Emerging evidence showed that radiotherapy combined with chemotherapy and PD-1 inhibitors led to promising tumor responses in patients (pts) with locally advanced rectal cancer (LARC). MIRACLE-1 aims to investigate the safety and efficacy of such approach as upfront treatment of MSS LARC with resectable metastases. Methods: MIRALCE-1 was a prospective, single arm, phase 2 study. The main inclusion criteria include MSS LARC with a distance of ≤10 cm from the anus by MRI evaluation and a limited number of metastases in the liver and/or lungs that were eligible for curable resection. Eligible patients were treated with upfront radiotherapy including hypofractionated radiotherapy (HFRT) for primary lesions and HFRT or stereotactic body radiotherapy (SBRT) for metastatic lesions. Afterwards, six cycles of systemic therapy consisted of CAPOX and Tislelizumab were administered. Then, reassessment was performed within 4 weeks afterwards by radiological and serological evaluations. Surgical resection, local ablative therapies or active surveillance was applied based on tumor response. For patients attained no-evidence of disease (NED), Tislelizumab was maintained until one year after surgery. Otherwise, the subsequent treatment was determined by the investigators. The primary endpoint is the 1-year NED rate. The secondary endpoints include objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and toxicities. Results: From March 2023 to November 2024, 38 pts were enrolled and 20 were evaluable. At baseline, 60.0% of pts were male, median age was 57 years (range 34-71), 55.0% had liver metastases (mets), 15.0% had lung mets, and 30.0% had both liver and lung mets. 80.0% primary tumors had RAS/BRAF mutations. Upon reassessment, 18 (90.0%) pts had partial response (PR) and 2 (10.0%) had stable disease (SD). No patients showed progressive disease (PD). The ORR was 90.0%. 65% (13/20) pts attained NED. Median PFS and OS have not yet reached. No grade 5 adverse events occurred. The most common treatment-related adverse events (TRAEs) in all grades were fatigue (85.0%), thrombocytopenia (65.0%), leukopenia (50.0%) and anemia (40.0%). The most frequent grade 3/4 TRAEs were thrombocytopenia (30.0%) and neutropenia (20.0%). Conclusions: Combination treatment of upfront radiotherapy, immunochemotherapy demonstrated a promising efficacy and a manageable safety profile in MSS LARC with resectable metastases. Translational study to identify predictive biomarkers is ongoing. Clinical trial information: NCT05359393 .

Duration of cCR in each individual patient who adopted WW

Representativeness of Study Participants

Postoperative complications according to Clavien- Dindo classification

e15521 Background: Liver metastasis remains a major hurdle to long-term survival of patients with rectal cancer. These patients with metastases could benefit from preoperative immunotherapy combined with conventional chemoradiotherapy. However, whether the metastatic baseline cellular microenvironment differs from the primary microenvironment and how they change after neoadjuvant therapy remain largely unexplored. Therefore, we used single-cell RNA sequencing to reveal cellular dynamics in primary rectal cancer and paired liver metastases. Methods: We obtained matched tumor samples from patients enrolled in the MIRACLE-1 (NCT05359393) and MIRACLE-2 (NCT05359406) studies before and after neoadjuvant therapy (n = 15, untreated rectal cancer; n = 4, untreated liver metastasis; n = 2, treated rectal cancer; n = 1, treated liver metastasis). Single-cell RNA sequencing was utilized to characterize the distinct immune microenvironment between primary rectal cancer and paired liver metastases. We also analyzed changes in primary and metastatic tumors between baseline and post-treatment samples. Results: The epithelial cells of primary tumors and liver metastases exhibited markedly different patterns of cell death following treatment. Higher proportions of CLEC10A + conventional type 2 dendritic cells (cDC2) and KLRB1 + mucosal-associated invariant T cells (MAIT) at baseline or increasing proportions during treatment were correlated with a better response to neoadjuvant therapy. PDGFRA + inflammatory cancer-associated fibroblasts (iCAFs), which could modulate T cell function via the GDF pathway, were absent in liver metastases compared to primary tumors prior to treatment (P < 0.01). Increased PDGFRA + iCAFs in the primary lesion after neoadjuvant therapy were associated with worse treatment efficacy. Conclusions: This study presents a single-cell atlas of MSS rectal cancer with liver metastases treated with radiotherapy followed by systemic therapy and Tislelizumab. The microenvironment of primary tumors and liver metastases differed at baseline and underwent distinct changes following treatment. Certain cell subsets, such as CLEC10A + cDC2, exhibited the potential to predict treatment efficacy. We are continuously collecting new patient samples to validate our findings and exploring their implications for clinical practice.