Yang et al. Anti-PD-1/CTLA-4 Dual Immunotherapy for LARC

According to the latest statistics from the National Cancer Center of China, theincidence and mortality of colorectal cancer rank 2nd and 4th among all malignant tumors,respectively. Locally advanced rectal cancer (LARC) accounts for more than 60% of allcolorectal cancer cases, predominantly presenting as mid‐low and locally advancedstages[1]. The standard therapeutic paradigm for LARC centered on "neoadjuvantchemoradiotherapy (NCRT) + total mesorectal excision + adjuvant chemotherapy" hassignificantly improved local tumor control, reducing local recurrence rate to below 5%and achieving pathological complete response (pCR) in a subset of patients[2]. Totalneoadjuvant therapy has also been widely applied in the treatment of high‐risk rectalcancer, with notable short‐term efficacy, yet its long‐term benefit remainscontroversial. The distant metastasis rate of rectal cancer reaches 25%‐30%, representinga critical determinant of prognosis.To further improve therapeutic efficacy, reduce distant metastasis risk, and enhancelong‐term prognosis, the oncological efficacy of neoadjuvant immunotherapy combined withchemoradiotherapy has been validated by an increasing number of multicenter randomizedcontrolled trials. The 2025 Chinese Society of Clinical Oncology (CSCO) Guidelines forthe Diagnosis and Treatment of Colorectal Cancer has listed neoadjuvant immunotherapycombined with chemoradiotherapy as a Grade II recommended regimen for pMMR/MSS rectalcancer. Multiple randomized controlled trials have demonstrated that neoadjuvantimmunotherapy combined with chemoradiotherapy can elevate the pCR rate from 15%‐20% to30%‐50%, allowing patients with clinical complete response (cCR) to adopt the"wait‐and‐watch" strategy for organ and function preservation[2‐4]. Despite remarkabletherapeutic outcomes achieved by neoadjuvant immunotherapy combined withchemoradiotherapy, several clinical research priorities and challenges remain to beaddressed through further investigation, including radiotherapy field selection, optimaltiming of immunotherapy initiation, clinical efficacy of different radiotherapyfractionation regimens, prediction of neoadjuvant immunotherapy response, and precisescreening of eligible candidates for the "wait‐and‐watch" strategy.Distant metastasis remains the primary challenge affecting long‐term prognosis of LARCpatients after neoadjuvant therapy[2]. In recent years, the synergistic effect betweenimmune checkpoint inhibitors and radiotherapy has provided a novel approach to overcomethis dilemma[1‐4]. Existing studies have shown that radiotherapy induces immunogenic celldeath, releases tumor antigens, activates the STING/cGAS pathway, promotes type Iinterferon secretion, and upregulates MHC‐I and PD‐L1 expression, thereby enhancing CD8⁺T cell infiltration, inhibiting immunosuppressive cell populations (e.g., Treg cells, M2macrophages), and improving the immune microenvironment[5]. Other studies indicate thathypofractionated radiotherapy (e.g., short‐course radiotherapy) exerts stronger DNAdamage and danger signal release effects, which not only promotes dendritic cellmaturation and antigen cross‐presentation but also causes less damage to peripheralimmune cells, facilitating the transformation of "cold tumors" to "hot tumors"[6].1.1 Exploration and Limitations of Long‐Course Chemoradiotherapy Combined withImmunotherapy Research on neoadjuvant long‐course chemoradiotherapy combined withimmunotherapy was initiated earlier, mainly comprising three modes: sequential,concurrent, and induction immunotherapy, yet its overall efficacy is inferior toshort‐course radiotherapy combined regimens. Regarding sequential immunotherapy: TheJapanese VOLTAGE‐A study first confirmed that sequential nivolumab after long‐courseradiotherapy increased the pCR rate to 30% in MSS LARC patients, with a grade 3 adverseevent rate of 11.9%[7]. The Chinese NECTAR study adopted long‐course radiotherapyfollowed by sequential tislelizumab for LARC, achieving a 40% pCR rate in 50 pMMRpatients with a 4% grade 3 adverse event rate, demonstrating the potential of drugoptimization[2]. Regarding concurrent immunotherapy: The Italian AVANA study investigatedconcurrent avelumab administration during long‐course radiotherapy, reporting a 23% pCRrate in 96 patients, suggesting that direct killing of immune cells by radiotherapy mayattenuate therapeutic efficacy[3]. Regarding induction immunotherapy: The US NRG‐GI002study employed a total neoadjuvant therapy modality, consisting of FOLFOX inductionchemotherapy followed by sequential long‐course radiotherapy plus pembrolizumab, whichyielded a 30.9% pCR rate with no significant difference compared with the control group.It was hypothesized that the immunosuppressive effect of induction chemotherapy mayoffset the combined efficacy[4]. Overall, the pCR rate of long‐course chemoradiotherapycombined with immunotherapy generally ranges from 23% to 40%, with limitations includinglong study duration, high time cost, potential attenuation of overall efficacy due toradiotherapy effects on lymphoid tissues, and possible suppression of peripheral bloodlymphocytes by chemotherapy.1.2 Breakthrough Progress of Short‐Course Radiotherapy Combined with Immunotherapy TheUNION study adopted the regimen of "short‐course radiotherapy + CAPEOX chemotherapy +camrelizumab" for mid‐low LARC, achieving a pCR rate of 39.8%, which was significantlysuperior to the 15.3% rate of traditional long‐course chemoradiotherapy, establishing thestandard therapeutic status of this regimen. The TORCH study employed the totalneoadjuvant therapy modality of "short‐course radiotherapy + CAPOX + toripalimab",reporting an overall CR rate of 55.4% in 121 LARC patients, with approximately 25% ofpatients achieving cCR and safely adopting the "wait‐and‐watch" strategy, while the pCRrate reached 50% in patients who underwent surgery[8]. The PRECAM study innovativelyapplied "sequential CAPEOX + envafolimab after short‐course radiotherapy", achieving apCR rate as high as 66.7% (12/18). Short‐course radiotherapy enhances tumorimmunogenicity through hypofractionated dose (5×5Gy), resulting in significantchemoradioimmunotherapy efficacy. However, acute toxicity within two weeks aftershort‐course radiotherapy is more pronounced compared with long‐course radiotherapy, andits biologically equivalent dose is lower than that of long‐course radiotherapy[9]. Theaforementioned studies have established the role of short‐course radiotherapy combinedwith chemotherapy and immunotherapy in the perioperative treatment of LARC, and thismodality demonstrates great potential for continuous optimization to further improveefficacy and reduce toxicity.1.3 Clinical Research Progress of Dual Immunotherapy in LARC pMMR/MSS rectal cancerexhibits low response to single‐agent immunotherapy. Dual immunotherapy has become aresearch focus, with its core mechanism lying in the amplification of anti‐tumor immuneresponse through multi‐target and multi‐pathway synergistic effects, thereby improvingoncological efficacy[10,11]. Theoretically, the PD‐1 pathway primarily acts in the tumormicroenvironment, relieving effector T cell functional suppression by blocking PD‐1/PD‐L1binding[12], while the CTLA‐4 pathway mainly functions during the initial activationphase of T lymphocytes in lymph nodes, inhibiting excessive immune responses[13]. Thecombination of these two agents enhances the breadth and depth of immune responses:CTLA‐4 blockade expands the "repertoire" of immune responses, whereas PD‐1 blockadeenhances the killing efficacy of effector cells against tumors[14,15].The NeoCaCRT study adopted the regimen of "sequential paromlimab and Tuvonralimabcombined with mFOLFOX6 after short‐course radiotherapy", achieving a 37% pCR rate and55.6% major pathological response rate in pMMR/MSS rectal cancer. This indicates thatneoadjuvant dual immunotherapy combined with chemoradiotherapy can provide clinicalbenefit even in pMMR/MSS rectal cancer[16]. Compared with single‐agent immunotherapy orimmunotherapy combined with chemotherapy, the theoretical advantage of dual immunotherapylies in activating effector T cells while simultaneously reversing the immunosuppressivemicroenvironment, which is particularly critical for pMMR/MSS rectal cancer.Despite promising signals from preclinical and some phase II studies, the application ofdual immunotherapy in LARC still faces multiple challenges. First, the issues of efficacyand population adaptability remain unresolved: current clinical benefits are mainlyderived from a small number of MSI‐H/dMMR patients, while the actual response rate andlong‐term benefit of dual immunotherapy in MSS/pMMR patients lack confirmatory evidence.Second, toxicity management is more challenging: the incidence of immune‐related adverseevents (irAEs) is significantly higher with the combination of PD‐1 and CTLA‐4 monoclonalantibodies compared with single‐agent therapy[6,17]. Third, the optimal combinationmodality and timing remain undefined: different studies show substantial variations inwhether to combine radiotherapy and chemotherapy, selection of short‐course orlong‐course radiotherapy, and timing of dual immunotherapy administration (concurrent orsequential), with no unified standard available[18]. Overall, dual immunotherapysimultaneously targeting PD‐1 and CTLA‐4 represents a novel approach in neoadjuvantimmunotherapy for LARC, demonstrating positive trends in organ function preservation andpCR. However, larger‐scale clinical trials with longer follow‐up periods are required toconfirm its actual value, and precise molecular typing and immunological characterizationshould be applied to screen eligible populations, ultimately promoting its developmentinto a mature regimen in the comprehensive treatment of rectal cancer.1.4 Core Controversies Regarding Dose, Field, and Timing of Immunotherapy Combined withChemoradiotherapy Based on the above analysis, although neoadjuvant immunotherapycombined with chemoradiotherapy exhibits significant advantages in improving local tumorcontrol, several critical issues remain to be addressed through targeted research. ‐ Selection strategy for short‐course vs. long‐course radiotherapy combined withimmunotherapy: Eligible populations, optimal timing of immunotherapy initiation, anddose adjustment strategies for different radiotherapy modalities (short‐course vs.long‐course) combined with immunotherapy require further clarification. ‐ Optimal timing and duration of immunotherapy: Based on our team's three‐armrandomized controlled study published in Nature Medicine in 2025, sequentialimmunotherapy is superior to concurrent immunotherapy, yet differences inoncological outcomes and safety between different combination modalities remaincontroversial, requiring identification of the optimal sequence of immunotherapy andchemoradiotherapy. ‐ Clinical application prospects of dual immunotherapy: Dual immunotherapy hasdemonstrated favorable oncological efficacy in single‐arm studies, but with smallsample sizes and low level of evidence, requiring further validation throughclinical research. ‐ Optimization of anus‐preservation strategy and screening of "wait‐and‐watch"candidates: Neoadjuvant immunotherapy combined with chemoradiotherapy significantlyincreases the cCR rate, enabling the "wait‐and‐watch" strategy[5]. How to preciselyscreen patients suitable for the "wait‐and‐watch" strategy through imaging andendoscopic evaluation to avoid overtreatment or delayed surgery remains a challengein clinical practice.This study focuses on the key challenges in the field of neoadjuvant immunotherapy forLARC. Through a prospective study comparing the efficacy and safety of differentradiotherapy fractionation modalities, immunotherapy initiation timings, and efficacyprediction models, this study aims to define the optimal treatment sequence and duration,optimize the anus‐preservation strategy and screening criteria for "wait‐and‐watch"populations, enhance local tumor control, reduce distant metastasis rate, improvelong‐term prognosis, provide individualized, highly effective, and low‐toxicity treatmentregimens for patients, and achieve the precise diagnosis and treatment goal of organ andfunction preservation.