Colorectal cancer (CRC) is one of the three most prevalent malignancies in the worldwide,¹ and most patients are diagnosed with metastatic colorectal cancer (mCRC). Advanced standard therapy in mCRC include regorafenib,² fruquintinib,³ and trifluridine-tipiracil (TAS-102).⁴ Although they achieved improvements in both progression-free survival (PFS) and overall survival (OS) compared with placebo, efficacy was still limited. Microsatellite instability (MSI) refers to variabilities in MS sequence length and base composition generated by insertion and deletion mutations during DNA replication. These modifications are usually connected with inadequate DNA mismatch repair function and accumulation of uncorrected MS replication errors.⁵ MSI tumors are classified into three groups by grade, namely MS stability (MSS), MSI-low (MSI-L), and MSI-high (MSI-H). Methods for diagnosing MSI include immunohistochemical study of MMR protein expression, multiplex polymerase chain reaction-capillary electrophoresis, and second-generation sequencing. Recently, immunotherapy is in full development. Pembrolizumab and nivolumab ± ipilimumab are authorised for patients with mismatch repair-deficient (dMMR)/MSI-H mCRC. However, around 5% of mCRC are dMMR/MSI-H⁶ whereas the remaining 95% are mismatch repair proficient (pMMR)/MSS. The phase II clinical trial, KEYNOTE-016,⁷ found that the objective response rate (ORR) in patients with dMMR/MSI-H mCRC and pMMR/MSS mCRC was 40% and 0%, respectively. How to break through resistance to immunotherapy in patients with pMMR/MSS mCRC has been a research priority. In 2019, the REGONIVO study⁸ resulted in a new era of immunotherapy for patients with pMMR/MSS mCRC. Subsequent investigations of fruquintinib in association with sintilimab,⁹ the LEAP-005 study¹⁰ and the CAMILLA study¹¹ indicated that a tyrosine kinase inhibitor (TKI) in combination with immunotherapy is effective in patients with pMMR/MSS mCRC. However, the REGONIVO study (North America),¹² the REGONIVO Plus study,¹³ the REGOTORI study¹⁴ and the Regomune research¹⁵ failed to do again the excellent ORR of REGONIVO (Japan). The ORR in these studies ranged from 7% to 27%, the disease control rate (DCR) was 39%–80%, and the median OS (mOS) was 7.5–15.5 months. Subgroup afrom the REGONIVO (North America) and REGONIVO Plus trials also found that patients with pMMR/MSS mCRC with liver metastases had modest responses and did not respond to immunotherapy. Therefore, in patients with pMMR/MSS mCRC with local metastases, specifically liver metastases, combined local treatment based on immunotherapy seems to be a research route worth pursuing. Many recent trials employing immunotherapy in combination with local therapy in the treatment of hepatocellular carcinoma have given encouraging findings. For example, the ORR in the Cal Era study¹⁶ was 80%, but the ORR in the non-alcoholic steatohepatitis hepatocellular carcinoma trial was 41.5%.¹⁷ However, this has not been fully studied in patients with pMMR/MSS mCRC with local metastases. In this study, we provide an overview of the advances in the combination of immunotherapy with local therapy, including radiotherapy, radiofrequency ablation, and transcatheter arterial chemoembolization (TACE), in the treatment of pMMR/MSS mCRC (Table 1) and discuss the prognostic biological landmark.

Table 1 . Results of Clinical Trials of Immunotherapy Combined with Local Therapy in the Late-Line Treatment of pMMR/MSS mCRC.

	Study name
	Fruquintinib + tislelizumab + SBRT (FRIUT)	Fruquintinib + sintilimab + RT	PD-1 inhibitor + RT + GM-CSF	Ipilimumab + nivolumab + RT (C2D1)	Ipilimumab + nivolumab + RT (C1D1)	Durvalumab + tremelimumab + RT	Durvalumab + tremelimumab + RFA/SBRT
Publish time	2023 ASCO-GI	2023 AACR	2022 ASCO	2022.5.18	2023 ASCO	2021.1.27	2023 ASCO-GI
MSI status	MSS	MSS	MSS	MSS	MSS	MSS	MSS
Line of therapy	≥ Third-line	≥ Third-line	-	≥ Third-line	≥ Third-line	≥ Third-line	≥ Third-line
PS status	-	-	-	0 (65%)/1 (35%)	0/1	0 (25%)/1 (75%)	-
Regimen	Fruquintinib (5 mg, QD, PO, day 1–14); tislelizumab (200 mg, day 1, IV); SBRT (8–10 Gy × 5 F, QOD)	Fruquintinib (QD, PO, day 1–14); anti-PD-1 (200 mg, day 1, IV); patients with isolated or localized metastasis will receive RT	RT (5 or 8 Gy × 2–3 F) for one metastatic lesion, PD-1 inhibitor dosing within 1 week RT, GM-CSF 200 μg subcutaneous injection QD for 14 days (day 1–14), or GM-CSF 200 μg (day 1–7), and then followed by IL-2200 million IU SC QD for 7 days (day 8–14)	Ipilimumab (1 mg/kg every 6 weeks for the first 4 cycles); nivolumab (240 mg every 2 weeks on a 6-week cycle); RT with 24 Gy/3 fractions to one site starting on C2D1	Ipilimumab (1 mg/kg every 6 weeks for the first 4 cycles); nivolumab (240 mg every 2 weeks on a 6-week cycle); RT with 24 Gy/3 fractions to one site starting on C1D1	Durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus RT	Tremelimumab 75 mg and durvalumab 1,500 mg for 4 cycles followed by durvalumab 1,500 mg every 4 weeks During cycle 1, RFA and SBRT were performed concurrently
Enrolled number	23	25	9	27	30	24	21
ORR (%)	26	28.0	22.2	15	13	8.3	-
DCR (%)	83	80.0	66.7	37	33	-	-
mPFS (mo)	5.1	6.05	5.6	2.5	2.4	1.8	-
mOS (mo)	Not reach	-	-	10.9	10.6	11.4	2.2

RT, radiation therapy; SBRT, stereotactic body radiation therapy; SIRT, selective internal radiation therapy; SABR, stereotactic ablative radiotherapy; CRT, conventional radiotherapy.

We searched PubMed (www.ncbi.nlm.nih.gov/pubmed) for full-text articles from 2017 to May 31, 2023, using the keywords “colon,” “cancer,” “immunotherapy,” “local treatment,” and “microsatellite stability.” The full-text articles found were carefully examined. In addition, all abstracts presented at international conferences between January 2020 and October 2023 were examined.

Abscopal effects generated by radiation treatment suggest that radiation therapy (RT) is directly related to the immune milieu and the patient’s immunological status.¹⁸ Typically, cancer cell antigens are generated during RT and are detected by dendritic cells (DCs), which upon activation bind these antigens to T cells, leading to T cell activation, and circulating T cells infiltrate tumors and interact with cancer cells. Antigen binding boosts the immune system mediated cell death. Therefore, the synergistic mechanism of radiation treatment in combination with immunotherapy may be broken into three points:

1. RT enhances the synthesis and presentation of tumor-associated antigens: Major histocompatibility complex (MHC)-1 is a key molecule for antigen recognition by CD8+ T cells. Although its expression is severely suppressed in malignancies,¹⁹ radiation may boost its expression.²⁰ In addition, local high-dose radiation may increase antigen presentation by DCs.²¹

2. Radiation treatment induces an immunological response: RT kills tumor cells, stimulating the development of “in situ vaccines” that in turn enhance the body’s early immune response.²² DCs may exhibit necrotic cell products such as DNA fragments as antigenic substances to CD8+ cells. Cell necrosis and DNA damage induced by RT may improve antitumor immunity.²³

3. Radiation treatment influences the tumor microenvironment: RT may regulate and reprogram the tumor microenvironment, changing from an immunosuppressive phenotype to an immunostimulatory phenotype. Radiation may promote CD8+ T cell infiltration, and low-dose radiation might cause normalization of tumor vasculature and polarization of M2 macrophages to M1 iNOS+. iNOS+ macrophages stimulate the production of Th1 chemokines, attract CD8+ and CD4+ T cells to tumor, and promote T cell-mediated anticancer effects.²⁴ The combination of programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) may convey inhibitory signals and restrict the proliferation of CD8+ T cells in lymph nodes. Some investigations have showed that PD-L1 expression on the surface of tumor cells will greatly increase after radiation.²⁵ Another study found that after RT, tumor create fragments of genetic material, such as double-stranded DNA, which trigger the cGAS-STING pathway and upregulate PD-L1 expression in tumor cells, enabling the tumor to evade the immune system.²⁶ In preclinical CRC models, radiation increases blockage of a single immune checkpoint,²⁷ changing immunotherapy-resistant malignancies to immunoreactive tumor.²⁸ A recent study indicated that radiation to the liver may destroy immunosuppressive macrophages, enhance the survival rate of liver T cells and minimize the “siphon effect” of liver T cells. Another investigation suggested that liver metastases may impair the efficiency of systemic immunotherapy.²⁹ In rare instances, RT may also boost the activity of immunosuppressive drugs. One investigation found that radiation may create a large rise in the number of regulatory T cells (Treg).³⁰

A prospective cohort study of fruquintinib in combination with sintilimab in the treatment of patients with pMMR/MSS mCRC was published at the 2023 American Association for Cancer Research meeting.³¹ A total of 55 patients were recruited, 25 treated with radiotherapy and 30 patients not treated with radiation.

ORR, DCR, and median PFS (mPFS) in the overall population were 16.4%, 56.3%, and 3.58 months. However, the results differed greatly between the radiation and non-radiotherapy groups, with ORRs of 28.0% and 6.7%, respectively (odds ratio [OR] = 7.344, P = 0.039, radiotherapy group against radiotherapy group). Without radiation, same below, DCR was 80.0% and 36.7% (OR = 7.991, P = 0.010), respectively, and mPFS was 6.05 and 2.60 months, respectively (HR = 0.286, P < 0.05). The mPFS of the radiotherapy + antiangiogenic + immunotherapy group was considerably better than that of the antiangiogenic drug + immunotherapy group (5.0 vs. 4.3 months, P = 0.065). No treatment-related deaths were reported, and one patient in the combined radiotherapy group developed curable radiation pneumonitis. This suggests that the addition of radiation to patients with pMMR/MSS mCRC may considerably improve the survival benefit of antiangiogenic in combination with immunotherapy.³² Meanwhile, Parikh et al,³³ a professor at Massachusetts General Hospital, reported that patients with pMMR/MSS mCRC who received radiotherapy in combination with ipilimumab and nivolumab³³ had a much-improved prognosis. A total of 40 mCRC patients were enrolled (one CRC patient had disease control status before enrolment, the other had progressive disease [PD]), with a DCR of 25% (10/40; 95% confidence interval [CI] 13%–41%) and an ORR of 10% (4/40; 95% CI 3%–24%), mPFS was 2.4 months (95% CI 1.8–2.5 months) and mOS was 7.1 months (95% CI 4.3–10.9 months). In the 27 patients who had radiation, DCR was 37% (10/27; 95% CI 19%–58%), ORR 15% (4/27; 95% CI 4%–34%) and mPFS 2.5 months (95% CI 2.3–2.8 months), mOS was 10.9 months (95% CI 6.7–15.0 months). Of note, large early withdrawals (progression, toxicity and reduction in performance status) were detected in this trial. Radiation treatment in the aforementioned study was commenced with Cycle 2 Day 1, and one-third of patients underwent RT. A phase II trial of nivolumab and ipilimumab was done to confirm this issue and minimize dropout before radiotherapy, with treatment being shifted to Cycle 1 Day 1 (C1D1). Poster 3584 (NCT04361162)³⁴ at the 2023 American Society of Clinical Oncology (ASCO) meeting revealed similar early results in a total of 30 patients with pMMR/MSS mCRC who had nivolumab and ipilimumab in combination with RT (24 Gy per site/3 fractions started at C1D1). This study exhibited an ORR of 13% (4/30; 95% CI 4%–31%), a DCR of 33% (10/30; 95% CI 17%–53%), and mPFS of 2.4 months (95% CI 1.8–2.9 months), mOS was 10.6 months (95% CI 6.8–17.8 months). In addition, 16 people developed ≥ 3. Grade 4 treatment-related severe side events, including lymphopenia (n = 3, grade 4), anaemia, and diarrhoea. The use of radiation started with C1D1 has proven favorable results in individuals with immunoresistant pMMR/MSS mCRC. Research into optimal radiation treatments such as radiotherapy fractionation (high or conventional), dose (high or low), selection of radiotherapy target (burden and organ) and sequencing (induction or concurrent) is undertaken. A pooled analysis of data from two phase II clinical trials³⁵ revealed that PD-1 inhibitors in concert with radiotherapy and granulocyte-macrophage colony-stimulating factor (with or without interleukin 2) were beneficial in patients with pMMR/MSS mCRC what a healing influence. A total of 9 patients were enrolled. All patients completed at least two treatment cycles and one assessment with a median follow-up of 7.6 months (95% CI 3.8–11.4 months), ORR 22.2%, DCR 66.7% and mPFS 5.6 months (95% CI 1.5–9.7 months). Treatment-related adverse events occurred in 7 of 9 persons (77.8%). One patient (11.1%) experienced grade 3 renal failure. The FRUIT study³⁶ presented at the 2023 ASCO-gastrointestinal (GI) meeting showed 25 patients with pMMR/MSS mCRC who received fruquintinib (5 mg once daily orally on days 1–14 of a 21-day cycle) in combination with tislelizumab (200 mg treatment, intravenous, day 1, 21-day cycle) and stereotactic body radiotherapy (SBRT; 8-10 Gy × 5 fractions, every other day, 10 days). Of note, 52% of the studied patients had a single metastatic location, while the remaining had two or more metastatic locations. With a median follow-up of 7.8 months (95% CI 4.31–11.29 months), mPFS was obtained at 5.1 months (95% CI 0.77–9.63 months). Furthermore, ORR was 26% and DCR was 83%. Regarding safety, most adverse reactions were grades 1–2, and the incidence of grade 3–4 adverse reactions was only 17%.

The PFS and OS in this study are excellent in the treatment of advanced mCRC, although due to the limits of the single-center phase II, the sample size needs to be further increased to demonstrate the usefulness of this regimen. Other study imply that immunotherapy with local irradiation may boost the efficacy of pMMR/MSS mCRC, and based on this, the combination of antiangiogenic drugs might create a better prognosis. Other study indicates different conclusions. One study evaluated 19 patients with pMMR/MSS mCRC and liver metastases who had subcutaneous veltomod, and tree intratumoral veltomod injections, radiosurgery in combination with nivolumab anti- and ipilimumab therapy. All but one patient had a non-responder, which was connected to a high tumor mutayion burden.³⁷ A single-center phase II study³⁸ enrolled 24 patients with pMMR/MSS mCRC having radiotherapy in combination with durvalumab and tremelimumab reported an ORR of 8.3%, mPFS of 1.8 months, and mOS of 11.4 months. The combination regimen tested in this study did not fulfil the prespecified primary end point. A phase I clinical trial³⁹ showed 9 patients with pMMR/MSS mCRC and liver metastases who received Y90 hepatic radioembolization followed by durvalumab and tremelimumab. All individuals were tested for PD at or after two cycles and the experiment was discontinued early. Flow cytometry results did not imply a role for Y90 radioembolization in the conversion of “cold” tumors to “warm” tumors. In a study of patients with mCRC who received a PD-1 inhibitor (AMP-224) in combination with low-dose cyclophosphamide and SBRT,⁴⁰ 5 out of 15 patients with liver metastases were excluded for accelerated disease progression. Neoadjuvant treatment is one of the key areas of application for immunotherapy in combination with RT. There are significant developments worth paying attention to, which are briefly addressed here. Many studies have employed immunotherapy with concurrent chemotherapy (CCRT) with positive early results. In the VOLTAGE study,⁴¹ 39 patients with pMMR/MSS and locally advanced rectal cancer (LARC) were sequentially recruited and given nivolumab after regular CCRT. Of these patients, 11 (29.7%) had a pathologic complete response (pCR). Further evaluation of molecular markers suggested that the ratio of CD8+ lymphocytes to CD45RA-FoxP3+ effector Treg cells in tumor-infiltrating lymphocytes (CD8/eTreg ≥ 2) and PD-L1 expression was > 1% in 6 patients, of which 5 patients reached a pCR. One patient obtained a pCR-clinical complete response without surgery. The AVANA study⁴² enrolled 101 patients with LARC who received avelumab sequentially after standard CCRT. Only 1 patient declined surgery. The pCR rate was 23% who underwent surgery, including 39 of 40 patients with MSS for whose microsatellite status was known. Both of the prior studies demonstrated considerably higher historical pCR rates (15%–18%) with neoadjuvant treatment. In addition, a phase II single-arm study included short-course radiation followed by two cycles of neoadjuvant therapy with XELOX + camrelizumab. The PCR rate in 26 MSS patients was 46.2%, which was also more than previously reported. However, the NRG-GI002 study⁴³ adopted a wholly neoadjuvant therapy technique. The experimental arm got capecitabine + pembrolizumab + radiation treatment, while the control arm received capecitabine + RT. Therefore, the pCR rates of the control arm and the experimental arm were 29.4% and 31.9%, respectively, and the difference was not statistically significant (P = 0.75). In the latest ASCO-GI 2023 report, the 3-year OS rate of the experimental group was larger than that of the control group. In summary, it is vitally essential to explore possible biomarkers connected with radiation treatment in combination with immunotherapy.

Radiofrequency ablation contains an electrical circuit created by an electrode needle injected into the tumor tissue and an electrode pad attached to the patient’s body. When the generator is turned on, a high-frequency current is injected into the target tissue. It not only increases local coagulation necrosis of tumors, but also forms vast amounts of tumor pieces, hence provoking anticancer immune responses.⁴⁴ Its synergy mechanism may be split into the following five points:

1. Lower immunosuppression: Radiofrequency ablation may promote tumor degeneration and necrosis, lower tumor burden and production of immunosuppressive chemicals, and minimize immunosuppressive effects on the host.⁴⁵

2. Improve exposure to tumor antigens: Radiofrequency ablation may kill tumor cells, expose a considerable number of tumor antigens, boost the antigenicity of tumors, and operate as a “tumor vaccine.”⁴⁶

3. Enhance immunogenicity against tumor antigens: Heat shock protein (HSP) is a type of peptide-binding protein that can be used as a carrier or peptide partner to combine with tumor antigens to form an HSP complex, present tumor antigens through MHC-I, and activate CD4+/CD8+ T cells and induce specific cellular immunity against specific tumor cells.⁴⁷ In mice with malignancies, radiofrequency ablation generated coagulation necrosis in the core ablated area, although HSP70 expression was substantially elevated in peripheral nonlethal lesions. In patients with hepatocellular carcinoma, the expression of HSP70 after radiofrequency ablation was 8 times higher than before surgery. High temperature may improve the expression level of HSP70 and HSP90 in hepatocellular carcinoma cells and promote the immune response to cancer cells.⁴⁸

4. Activated antigen-presenting cells: DCs are the most efficient antigen-presenting cells in the body. Mature DCs may activate naïve T cells and resting T cells by presenting antigens and creating costimulatory signals that prepare antigen-specific T cells to destroy tumors. In tumors with small and non-functional DCs, they cannot effectively transmit tumor antigens and cannot efficiently induce local tumor-specific cytotoxic T-lymphocyte responses.⁴⁹ Radiofrequency ablation may activate DC and enhance certain anticancer actions of T cells.⁵⁰

5. Increase the number of tumor-specific T cells: CD8+ T and natural killer (NK) cells are the major effector cells of tumor immunity and may directly destroy tumor cells. After tumor ablation, tumor-specific CD8+ T and NK cells may accumulate in the border tissues of necrotic lesions, which might further strengthen the specific anticancer effect.⁴⁵ Immunotherapy improves the anti-tumor immune response by reversing the decline of T cell activity and restoring immune system recognition and immunological attack. Therefore, the anticancer impact of radiofrequency ablation in combination with immunotherapy is greatly intensified, and the combined treatment will obtain a therapeutic additive effect.

Shi et al⁵¹ treated a mouse model with radiofrequency ablation and PD-1 monoclonal antibody against CRC. The data demonstrated that there was a big boost in tumor antigen expression, an improvement in the killing of T cells, and a significant increase in the proportion of effector T cells in distant tumors. A non-randomized phase II clinical research⁵² enrolled 26 patients with pMMR/MSS mCRC who received pembrolizumab with palliative radiotherapy (group 1) or radiofrequency ablation (group 2). The median ORR in Cohort 1 was 9% (1/11), however no response was reported in Cohort 2. In addition, 73% of patients experienced drug-related adverse effects; however, all were of grade 1 or 2. A phase II clinical study (ASCO-GI 2023 Poster 141)⁵³ assessed 23 patients with pMMR/MSS mCRC treated with durvalumab and tremelimumab in combination with radiofrequency ablation or SBRT. Median follow-up was 11 months, mPFS was 2.2 months, 55% of patients died during follow-up, and the trial was discontinued early. Of the 13 patients who received radiofrequency ablation, 30.8% had grade 3 toxicity. A retrospective investigation⁵⁴ demonstrated no objective response to regorafenib in association with an anti-PD-1 antibody, demonstrating poor clinical effectiveness in unselected Chinese patients with pMMR/MSS mCRC. However, one of the patients who got radiofrequency ablation for liver and abdominal wall metastases before combination therapy reached a PFS of 9.2 months with stable disease (SD). Therefore, the combination of TKI-based radiofrequency ablation and immunotherapy seems to be a more effective treatment strategy for patients with pMMR/MSS mCRC in association with liver metastases. Although the outcomes of clinical research tend to suggest that the effect of immunotherapy paired with radiation and ablation is not optimum, it needs to be observed whether a long-term TKI combination may further boost survival.

TACE principally acts on the antitumor by selectively embolizing tumor arteries, enhancing the concentration of antitumor drugs in the local lesion and maximizing the incidence of ischemic necrosis. Depending on the cause of the embolism, TACE is categorized into conventional TACE (cTACE) and drug-eluting bead TACE (DEB-TACE). cTACE comprises tumor artery embolization utilizing lipiodol medication and particle embolization agents, whereas DEB-TACE necessitates tumor artery embolization employing drug-eluting microspheres preloaded with chemotherapeutic drugs. Like radiofrequency ablation, TACE-induced necrotic cell death may possibly generate a systemic immune reaction. Studies have showed that TACE may generate a decline in Treg cells⁵⁵ and an increase in AFP-specific CD4+ T cells⁵⁶ in liver cancer, therefore enhancing immunological responses and inflammatory responses in the microenvironment. In addition, systemic immune responses may be produced by altering the phenotype of peripheral immune cells.⁵⁷ Liver tumor cells are extremely sensitive to radiation. Under the action of radiation, tumor cells not only generate modifications in the tumor microenvironment, but also experience apoptosis and create immunogenicity, which further amplifies the fatal impact of immune cells on tumor tissue.^58,59

Although TACE in combination with immunotherapy and TKI had outstanding results in advanced liver cancer,⁶⁰ there are few studies in patients with mCRC and liver metastases. Currently, research have disclosed the consequences of TACE in combination with TKI. A single-center observational trial⁶¹ examined the efficacy and safety of the combination of regorafenib with DEB-TACE in patients with CRC with liver metastases (MSI status non-defined). There were 42 patients in the regorafenib group and 34 in the regorafenib + DEB-TACE group. The regorafenib + DEB-TACE group outperformed the regorafenib group in terms of PFS (median: 7.6 against 4.1 months, P < 0.001), OS (median: 15.7 compared 9.2 months, P < 0.001), ORR (35.3% vs. 7.1%, P = 0.002), and DCR (76.5% against 47.6%, P = 0.011). Patients with CRC and liver metastases may have a better response rate and a longer survival time when regorafenib and DEB-TACE are administered together. Hepatic arterial infusion chemotherapy (HAIC) with regorafenib was employed in a study published at the 2021 ASCO meeting to treat patients with mCRC and liver metastases (MSI status not defined).⁶² The patients had an OS of 22.2 months and an ORR of 51.3%, suggesting that this regimen is helpful in treating liver metastases in mCRC. The efficacy of DEB-TACE in conjunction with HAIC for unresectable CRC with liver metastases was explored by a single-center retrospective study that was reported at the 2023 ASCO meeting. The OS was not yet achieved for patients refractory at second lines liver PFS and PFS were 6.2 (95% CI 4.899–7.501) and 5.2 (95% CI 3.682–6.718) months, respectively. This shows that HAIC and DEB-TACE are promising. In the future, another investigation is planned to evaluate the use of immunotherapy in conjunction with TACE/HAIC in patients who have liver metastases and pMMR/MSS mCRC.

International clinicians are aiming to combine immunotherapy with chemotherapy and target treatment to change cool tumor into hot ones. None of these studies have provided encouraging findings. We’ve mentioned some advancements in immunotherapy in conjunction with local treatment, but it’s crucial to exercise prudence when judging whether this combination can increase outcomes and lengthen patient lives. There are many local therapy strategies accessible; the greatest one is yet to be identified. Different metastatic sites react differently to the same combination therapy. Currently, most clinical trials do not give detailed stratified data; accordingly, additional time is essential to acquire improved accuracy. We hope that more research will be done in the future to conduct other phase II/III trials. It’s intriguing to understand whether this combination treatment may constitute an innovation in perioperative, conversion, and first-line therapy, in addition to late-line treatment.

There are now active small-sample studies (Table 2) exploring immunotherapy and local therapy as the late-line treatment; combined radiotherapy appears like a good approach to pursue. These clinical trials may provide significant insights and aid for future clinical research. In the future, immunotherapy is expected to be applied to treat pMMR/MSS mCRC. Larger sample sizes for clinical trials and real-world research are thus essential.

Table 2 . Ongoing Clinical Trials of Immunotherapy Combined with Local Therapy in the Late-Line Treatment of pMMR/MSS mCRC Registered on Clinicaltrials.Gov.

Study name/ID	Intervention	Target	CRC study population	Phase	Status
NCT04535024	SABR + sintilimab	PD-1; ablation	MSS oligometastatic CRC	II	Recruiting
NCT04030260	Regorafenib + PD-1 antibody + radiotherapy ± SABT	PD-1; VEGFR; radiotherapy	MSS metastatic CRC	II	Recruiting
NCT04575922	Ipilimumab + nivolumab + RT	PD-1; CTLA-4; radiotherapy	Metastatic MSS CRC	II	Active, not recruiting
NCT03104439	Nivolumab + ipilimumab + RT	PD-1; CTLA-4; radiotherapy	MSS and MSI high CRC	II	Recruiting
NCT05292417	Sintilimab + GM-CSF + fruquintinib + radiotherapy	PD-1; VEGFR; radiotherapy	MSS metastatic CRC	II	Recruiting
NCT05160727	Tislelizumab + irinotecan + radiotherapy	PD-1; radiotherapy; chemotherapy	MSS inoperable recurrent and metastatic CRC	II	Recruiting
NCT04659382	SIRT + XELOX + bevacizumab + atezolizumab	PD-1; VEGFR; radiotherapy; chemotherapy	MSS mCRC with predominantly non-operable liver metastases	II	Recruiting
NCT04108481	Yttrium-90 radioembolization + durvalumab	PD-1; radiotherapy	Liver-predominant, MSS metastatic CRC	I/II	Suspended (working on revisions)
NCT03802747	Durvalumab/durvalumab and tremelimumab + SIRT/SBRT	PD-1; CTLA-4; radiotherapy	Liver metastases for patients with MSS CRC	I	Withdrawn (PI left the institution)
NCT05438108	SBRT + CapeOX + bevacizumab + sintilimab	PD-1; VEGFR; radiotherapy; chemotherapy	MSS metastatic CRC	II	Recruiting
NCT02437071	Pembrolizumab + radiotherapy/ablation	PD-1; radiotherapy; ablation	Metastatic CRC	II	Active, not recruiting
NCT04924179	Fruquintinib + tislelizumab + SBRT	PD-1; VEGFR; radiotherapy	Metastatic CRC	II	Active, not recruiting
NCT05635149	Fruquintinib + PD-1 antibody + CRT/SBRT	PD-1; VEGFR; radiotherapy	MSS metastatic CRC	Observational cohort study	Recruiting
NCT02888743	Durvalumab + tremelimumab + high or low dose RT	PD-1; CTLA-4; radiotherapy	MSS metastatic CRC	II	Active, not recruiting
NCT05894837	Serplulimab + regorafenib + hepatic artery bicarbonate infusion	PD-1; chemotherapy; hepatic artery bicarbonate infusion	Metastatic CRC liver metastases	II	Active, not recruiting

RT, radiation therapy; SBRT, stereotactic body radiation therapy; SIRT, selective internal radiation therapy; SABR, stereotactic ablative radiotherapy; CRT, conventional radiotherapy.

We thank all the authors for their contribution.

None.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

No potential conflict of interest relevant to this article was reported.