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. 2025 Jul 12;17(10):727–734. doi: 10.1080/1750743X.2025.2530853

Predictive biomarkers for immune checkpoint inhibition for patients with colorectal cancer: a comprehensive review

Ibrahim Halil Sahin a, Turcin Saridogan b, Richard Kim c,✉
PMCID: PMC12355713  PMID: 40652318

ABSTRACT

Immune checkpoint inhibitors have resulted in treatment paradigm changes for the management of patients with solid tumors, including microsatellite instability-high (MSI-H) colorectal cancer (CRC). Although the benefit of these agents appears to be limited for microsatellite stable (MSS) CRC, recent studies suggest that the immune microenvironment of the early-stage MSS CRC and perhaps those with advanced-stage disease without active liver metastasis may be more immune permissive where relatively more promising responses were noted. At this time, biomarkers of immunotherapy for patients with CRC have not been well-defined. Except for the loss of mismatch repair protein (MMR) function and POLE/POLD1 mutations, most of the biomarkers of response are largely investigational. In this review article, we summarize recent research and drug development with immune checkpoint inhibitors for patients with MSS and MSI-H CRC and elaborate on investigational biomarkers, including but not limited to tumor mutation burden and immunoscore. We also discuss the relevance and potential applicability of these biomarkers to clinical practice for the use of immune checkpoint inhibitors and provided further perspective on future biomarker development.

KEYWORDS: Immune checkpoint inhibitors, colorectal cancer, biomarkers, tumor mutation burden, T cells, B cells

Plain Language Summary

The benefit of immunotherapy is predominantly seen among patients with mismatch repair-deficient colorectal cancer, and the benefit is relatively limited among patients with advanced mismatch repair proficient colorectal cancer. However, early studies suggest the benefit may be more notable among patients with early-stage colorectal cancer when used before surgical excision of the tumor. There are no well-established biomarkers for immunotherapy for patients with colorectal cancer, except mismatch repair status and mutations causing defects in genes named POLE and POLD1. The total amount of mutations seen in tumors does not appear to be a good biomarker for patients with mismatch repair proficient colorectal cancer, and more research is needed for other biomarkers looking at immune cells in the immediate surroundings of cancer cells.

1. Introduction

Colorectal cancer (CRC) is the most common type of gastrointestinal cancer and represents one of the leading causes of cancer-related mortality in the United States and the World with increasing incidence in young population [1]. Recent national cancer statistics indicate that CRC is now the leading cancer-related cause of death among young males aged 20–49. A similar trend is also seen in young adult females, indicating that CRC will remain a challenging cancer for Western countries for decades to come [1,2]. Notably, CRC is composed of a biological and clinically heterogeneous subset of disease with distinct molecular signatures leading to varying clinical outcomes. Genetic underpinnings of CRC can be categorized into two main groups: those with chromosomal instability [3], which represents the majority of cases, and those with microsatellite instability [4], which is a relatively smaller fraction of the overall CRC population. These two molecularly highly distinct subgroups resulted in the evolution of highly different treatment paradigms for patients with advanced-stage disease CRC.

The current standard of care systemic therapy for patients with advanced-stage microsatellite instability-high (MSI-H)/mismatch repair deficiency (MMR-D) CRC and locally advanced MSI-H/MMR-D rectal cancer is immune checkpoint inhibitors [5–7]. Similarly, immune checkpoint inhibitors have resulted in significant improvement in survival outcomes of patients with locally advanced colon cancer when it is given as neoadjuvant therapy [8] and the recent data from of ATOMIC trial showed that the addition of atezolizumab to adjuvant chemotherapy resulted in improved 3-year disease free survival (DFS) with an absolute benefit of 9.8% (HR, 0.50; 95% CI, 0.35 to 0.72) [9]. However, it remains unclear whether patients with MSI-H colon cancer even need chemotherapy given highly promising DFS outcomes noted in the NICHE-II trial with neoadjuvant immunotherapy alone. For patients with advanced-stage microsatellite stable (MSS)/Mismatch repair proficient (MMRp) CRC, immune checkpoint inhibitor therapies have achieved only little progress in chemotherapy-refractory setting [10–12] or as front-line therapy [13], while more benefit has been observed for patients with earlier stage of CRC [14,15]. Currently, several other novel immune checkpoint inhibitors are being investigated for patients with MSS/MMRp CRC to change the immune cold nature of this challenging disease and induce antitumor immune response.

Multiple studies have explored biomarkers for immune checkpoint inhibitor therapy in patients with MSI-H and MSS CRC, including tumor mutation burden, PD-L1 expression, and Immunoscore, yielding highly heterogeneous results. In this review article, we provide an overview of the recent advancements in immune checkpoint inhibitor therapy that resulted in rapid drug development in MSI-H CRC and ongoing efforts for patients with MSS CRC. We also discuss predictive markers of immune checkpoint inhibitors and their utility in clinical use, as well as other potential opportunities for future biomarker-based drug development with immune checkpoint inhibitors.

2. Predictive biomarkers of immune checkpoint inhibitor therapy for advanced-stage MSI-H CRC

Immune checkpoint inhibitors resulted in rapid progress in drug development and change in the treatment paradigm of patients with MSI-H CRC. The KEYNOTE 177 trial established pembrolizumab as one of the standards of care therapy as a front-line treatment based on improved PFS (16.5 vs 8.2 months) for patients with MSI-H CRC [16]. More recently, the CheckMate 8HW confirmed improved PFS outcomes with nivolumab and ipilimumab combination compared to nivolumab monotherapy and chemotherapy arm offering nivolumab and ipilimumab as another alternative standard of care therapy for front-line therapy, though at the cost of potentially increased toxicity [17] Notably, both studies showed deep and remarkably durable responses unlike historical relatively short responses seen with systemic chemotherapy for this subtype of CRC. Nonetheless, in both trials, there were patients who progressed either early in the course of the disease (de novo resistance) or later in the course (acquired resistance), indicating biological heterogeneity among patients with MSI-H CRC. Therefore, translation studies were conducted to better understand disease heterogeneity, resistance mechanisms, and biomarkers of response (Table 1).

Table 1.

Molecular and clinical biomarkers of immunotherapy investigated for MSI-H CRC.

Biomarker Cut-off investigated Biomarker role Clinical Role
PD-L1 Various, including 1% None None
TMB Various cutoffs were investigated (including 23 and 37.4) Yes May be associated with a better response to immunotherapy, although low TMB does not rule out benefit
CD8+ T cells at the invasive front or in TME NA Possibly Research only
B cells infiltration NA Possibly, for those with liver metastases Research only
BRAF V600E mutation NA Possibly (particularly for early-stage CRC) Maybe associated with inferior response
KRAS mutations NA Possibly Maybe associated with inferior response
Liver metastases NA Possibly Associated with inferior outcomes
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*MSI-H: microsatellite instability-High, **TMB: tumor mutation burden.

In one of the landmark studies, investigators evaluated the biomarkers of immune response among patients with MSI-H CRC who received pembrolizumab. Notably, PD-L1 expression, an immune checkpoint inhibitor biomarker for other diseases such as gastroesophageal cancers, was not associated with response to pembrolizumab [18]. Investigators identified neoantigen load and the presence of circulating neoantigen reactive CD8+ T cell infiltrate at the invasive front of the tumor as biomarkers of response [18]. The investigators also discovered an association between higher somatic mutation load and better progression-free survival. Another translation research of 22 patients with MSI-H CRC also identified high TMB (with a cutoff of 37.4 mutations/Mb) as a surrogate of response to immune checkpoint inhibitors as a response to therapy [19]. In this study, a correlation between neoantigen load and somatic mutation load, both of which are linked to immune response, was also noted. A recent large study of MSI-H CRC patients also reported a similar association between high TMB (defined as >23 mut/Mb) and improved outcomes, while early progression among patients with low TMB [20]. A study of patients with resectable liver metastasis who were treated with immune checkpoint inhibitors showed a complete response among those with MSI-H CRC and a correlation between improved progression-free survival and increased B cell density in addition to activation of CD8+ T cells [21]. BRAF V600E mutation is also associated with sporadic MSI-H/MMR-D CRC with distinct mechanisms, and it was also investigated as a surrogate of resistance given the biological impact of BRAF V600E mutation on cancer cells with increased MAPK-ERK activity, and while some studies indicated it might be associated with poorer response, some studies showed no difference [22,23]. In a recent large pooled analysis of real-world data, the loss of MSH2/MSH6 proteins was found to be associated with better response to immunotherapy [24]. In this study, the investigators also identified increased neoantigen load among patients with MSH2/MSH6, possibly explaining improved survival outcomes in this subset of MSI-H CRC. In the KEYNOTE 177 trial, the investigator observed relatively worse survival outcomes among patients with a KRAS mutation. However, the CheckMate 142 and 8HW studies did not reveal similar outcomes with KRAS mutation, and responses were similar across subgroups [25].

3. Predictive biomarkers of immune checkpoint inhibitor therapy for early-stage MSI-H CRC

Based on the promising response observed in advanced-stage MSI-H CRC, immune checkpoint inhibitors have also been investigated in localized colon and rectal cancers in several studies. NICHE-1/2 trials evaluated the efficacy of two doses of nivolumab with a single dose of ipilimumab as a neoadjuvant therapy for patients with MSI-H colon cancer. In both trials, dramatic pathological responses were noted, and the majority of patients had complete or major pathological responses defined as <10% viable tumors. Most recently, investigators reported 3-year DFS outcomes, which showed a 100% DFS rate [26]. In another trial, dostarlimab was investigated for patients with locally advanced MSI-H rectal cancer and reported 100% complete clinical response (cCR) among 12 patients enrolled in the study [7]. Most recently, they reported expanded cohort results which also showed 100% cCR among 41 patients enrolled in the study with durable responses [27].

Notably, both studies showed unprecedented treatment responses in the early stages of MSI-H CRC compared to advanced-stage disease, which may be at least partially due to distinct tumor microenvironments in primary tumors compared to metastatic disease, particularly in the liver. Recent studies identified that patients with liver metastasis had inferior outcomes compared to other sites of metastasis, providing further insight into the link between tumor microenvironment and antitumor immune response [22,28]. In the NICHE trial [15], the investigator identified significantly higher T cell receptor clonality in the primary tumor samples of the patients with MSI-H colon compared to MSS colon cancer, leading to significantly better outcomes. Expectedly, the authors also identified higher TMB and stem-like T cells (CD8+PD-1+ T cells) and CD8+ T cell infiltration in MSI-H colon compared to MSS colon cancer in pre-treatment samples, indicating that the immune signature of primary tumor of MSI-H is highly permissive for antitumor immune response. Notably, in post-treatment samples, the investigators identified increased CD8+ and CD3+ T cells, interferon-gamma signature, while T cell receptor clonality did not change, indicating preexisting T cell clones drive the response and immune checkpoint inhibitors may have limited impact on the T cell repertoire [15]. Unlike metastatic disease, the investigators did not identify any association between pathologic response and somatic mutation burden [8]. Notably, BRAF V600E mutation was associated with a lower incidence of complete pathological response compared to those without BRAF V600E mutation (75% vs 57%). Interestingly, BRAF mutation was not detected among patients enrolled in the study by Cercek et al. [7], perhaps explaining the high incidence of complete clinical response seen in this study. In the NICHE-2 trial, surprisingly, RAS mutations were associated with higher pathological complete response (79%) than those without a RAS mutation (64%) [8]. Similar to the NICHE trial, the NEST trial also demonstrated clonal expansion of CD3+/CD8+ T cells and CD20 B lymphocytes in the tumor microenvironment with dense inflammatory response orchestrated by adaptive immunity among responders (Table 1) [14,29].

Overall, the studies from the neoadjuvant space indicate that preexisting immune infiltrate, which is expanded by immune checkpoint inhibitors, results in unprecedented response rates in the early-stage colon and rectal cancer, leading to deep and durable pathological and clinical responses.

4. Predictive biomarkers of immune checkpoint inhibitor therapy for advanced-stage MSS/MMRp CRC

Immune checkpoint inhibitors have been investigated for patients with MSS/MMRp colorectal cancer to define their clinical benefit. So far, studies for patients with chemotherapy-refractory MSS/MMRp CRC have revealed that the response to immune checkpoint inhibitors is relatively limited, and modest response can be seen among patients without active liver metastasis with immune checkpoint inhibitor doublet therapies or with tyrosine kinase inhibitor combination [10,11,30,31]. Recently, a randomized phase III trial did not show any improvement in OS with the combination of pembrolizumab and lenvatinib compared to standard-of-care therapy [13]. Similarly, front-line chemotherapy and immune checkpoint inhibitor combinations did not reveal significant benefit [13]. Collectively, the lack of benefits from immune checkpoint inhibitor therapy in these studies is consistent with the biological immune cold nature of MSS colorectal cancer compared to MSI-H CRC.

4.1. The biomarker role of POLE/POLD1 in MSS CRC

POLE/POLD1 mutations are associated with ultramutated tumors with exceptionally high somatic mutations due to defective DNA polymerase function with loss of proofreading function causing accumulation of mutations during DNA synthesis [32]. These tumors often carry higher somatic mutations (>100 mut/Mb) than those with MSI-H CRC; however, these are often point mutations as compared to frameshift mutations that are seen in MSI-H CRC. Although frameshift mutations are more likely to induce neoantigen generation due to changes in the sequence, which represents the molecular underpinning of the immune response seen in patients with MSI-H CRC, the ultra-high mutations seen in POLE/POLD1 mutated MSS CRC can also change the equilibrium to “immune hot” tumor microenvironment leading to response to immunotherapy [32,33]. A large cohort study involving patients with CRC revealed improved overall survival with the use of immunotherapy among those patients with MSS CRC with POLE/POLD1 alterations compared to those without these alterations [33]. Similar studies also revealed the benefit of immune checkpoint inhibitor therapy among patients with MSS CRC [34], indicating the unique biomarker role of these alterations (Table 2).

Table 2.

Molecular and clinical biomarkers of immunotherapy investigated for MSS CRC.

Biomarker Cut-off investigated Biomarker role Clinical Role
PD-L1 Variable None when used solely None
TMB 10 mutations/Mb None except those with POLE/POLD1 TMB cutoff 10 has a very limited role for MSS CRC (both early- and advanced-stage)
Immunoscore NA Possibly Research only
Immunoscore IC (CD8+ T cell +PD-L1) NA Possibly Research only
POLE/POLD1 NA Yes Predictor of immunotherapy response
Non-liver metastases (particularly lung metastases) NA Possibly Associated with modest response
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*MSS: microsatellite stable, **TMB: tumor mutation burden ***POLE: DNA polymerase epsilon ****POLD-1 DNA polymerase delta.

4.2. TMB as a biomarker for MSS CRC

The FDA approved the use of pembrolizumab for patients with solid tumors and with TMB ≥ 10 mutations (mut)/Mb, including colorectal cancer, based on KEYNOTE-158, in which investigators showed an ORR of 29% [35]. Notably, the cohort of patients investigated in this study did not include patients with MSS CRC. Follow-up studies among patients with MSS CRC with TMB ≥ 10 mut/Mb did not show a similar benefit that was observed in KEYNOTE 158 [32,34,36]. The clinical utility of TMB without POLE/POLD1 mutations in MSS CRC is highly limited, and the use of immunotherapy for patients with MSS CRC is unlikely to yield benefits. It is important to recognize that the biology of each cancer is highly complicated due to molecular underpinnings and mechanisms that can directly impact immune response and the nature of the tumor microenvironment [37]. It is important to recognize that the tumor microenvironment of immune cold tumors, such as colorectal cancer, is highly different than “immune hot” tumors, and there are several factors beyond the load of somatic mutations that interfere with the function of the adaptive immune system such includes infiltration of myeloid-derived suppressor cells, increased T regulatory activity in the tumor microenvironment [38,39]. Therefore, the impact of TMB cutoff 10 mut/Mb on the immune response for MSS CRC appears to be limited, and it does not represent a reliable biomarker for immune checkpoint inhibitor therapy.

4.3. Immunoscore and PD-L1 as a biomarker in MSS CRC

Although MSS CRC is known to be an “immune cold” cancer, the heterogeneity in the immune profile of MSS tumor microenvironment and a score to define the immune population in the microenvironment, called immunoscore (a score to measure density of CD3 and CD8 + T cells), has been investigated and found to be associated with better outcomes and response to adjuvant chemotherapy [40–42]. AtezoTRIBE trial, in which atezolizumab was investigated in combination with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) and bevacizumab for patients with MSS CRC, conducted correlative analyses to define subgroups that therapeutic of this combination who may derive more benefit from this treatment by using a derivative of immunoscore [43]. In this trial, the investigators used a digital pathology platform to calculate immunoscore-immune checkpoint (Immunoscore IC) using CD8+ T cell density and PD-L1 expression collectively [43]. Notably, the trial showed significantly improved outcomes in the investigational arm (FOLFOXIRI plus atezolizumab) among patients with Immunoscore-IC high compared to those with Immunoscore-low (HR: 0.42 95% CI 0.21–0.85) indicating immune infiltration in the tumor microenvironment may serve as a potential biomarker for future clinical trials. It is important to note that this was a post-hoc analysis, and investigators are currently further evaluating this biomarker in clinical trials (NCT06733038) [43]. In this context, PD-L1 positivity was utilized as a biomarker in recent clinical trials, the RELATIVITY-123 trial, in which the investigators examined the efficacy of nivolumab and relatlimab combination and the trial did not show any benefit of this combination for patients with MSS CRC whose disease progressed on front-line therapies [44]. PD-L1 expression was also tested in other randomized clinical trials, and it was shown to be not associated with the benefits of immunotherapy [13]. Therefore, testing of PD-L1 expression as a biomarker for MSS CRC is not recommended and should be considered as an investigational biomarker.

5. Predictive biomarkers of immune checkpoint inhibitor therapy for early-stage MSS CRC

Although clinical trials with refractory and front-line settings did not result in practice-changing treatments, these agents were tested as a neoadjuvant therapy for colon cancer. In the NICHE-1 trial, investigators included patients with MSS colon cancer and observed 27% pathological response (defined as tumor regression > 50%), and among those, 20% of them had a major pathological response (less than 10% viable tumor) with only two doses of nivolumab and a single dose of ipilimumab indicating the difference in immune response in early-stage CRC and advanced-stage CRC [15]. In this study, investigators reported responses with low TMB, and it did not differ between responders versus non-responders, similar to advanced-stage MSS CRC [15]. Notably, the only biomarker that correlated with immune checkpoint inhibitor response for patients with MSS CRC was the T cells co-expressing CD8 and PD-1 [15]. In the NEST study, infiltration of CD8+ T cells and CD20+ B cells was noted among responders, which is consistent with other reports in the literature [29]. Overall, the more favorable tumor microenvironment of MSS CRC appears to be immune permissive with a reasonable response to immune checkpoint inhibitors, particularly for those with preexisting T and B cell clones, resulting in clonal expansion and antitumor effect. More translational research is warranted to better define potential biomarkers of immunotherapy response and to advance our understanding of the immune signature and dynamics of primary tumor of MSS CRC as compared to metastatic sites.

6. Future perspective

Immune checkpoint inhibitors have resulted in a rapid treatment paradigm of MMR-D/MSI-H CRC; the benefit of these agents for patients with MMRp/MSS CRC is relatively limited, particularly for those with advanced-stage disease. An exception is ultramutated MSS CRC due to POLE/POLD1 mutations, where the benefit of immunotherapy is promising. At this time, the value of tumor TMB as a biomarker of response appears to be more relevant to those with MSI-H CRC, while TMB itself does not seem to correlate with immune checkpoint inhibitor response among patients with MSS CRC without POLE/POLD1 mutations likely due to low antigenicity of point mutations seen in MSS tumors. It is important to note that frameshift alterations seen in MSI-H are more likely to create neoantigens than those with point mutations, which explains a better correlation with somatic mutation burden and better immune response in MSI-H CRC [32]. Similarly, PD-L1 expression stand-alone is not a predictor of the response to immunotherapy neither for MSI-H CRC nor for MSS [44]. At this time, limited data suggest that the immune composition of the tumor microenvironment may impact the response to immunotherapy, and further research is underway to better understand the biomarker role of CD4+/CD8+ T cells and CD20+ B cells for immunotherapy response (Figure 1). Overall, there is no well-established and well-studied immunotherapy biomarker for patients with MSS colorectal cancer that can be utilized in clinical practice, and further research in controlled studies can uncover the clinical utility of some of the biomarkers.

Figure 1.

Figure 1.

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Demonstration of the tumor microenvironment and intrinsic and extrinsic potential biomarkers including tumor mutation burden and immune infiltrate (created in BioRender. saridogan, T. (2025) https://BioRender.com/0yd7g8k).

At this time, there is a significant unmet need for research on biomarker development as well as the molecular underpinnings of immune response with the use of these novel agents. Significant variability exists in biomarkers like PD-L1 expression and TMB across tumor types, reflecting the complexity of immune responses. Future research should prioritize studying the unique biology and microenvironment of each tumor type to develop precise, tumor-specific biomarkers. Therefore, disease-agnostic, generalizable biomarker development, and investigational therapeutics without consideration of molecular features and the immune microenvironment of each cancer will unlikely lead to precise biomarker identification. Studies should consider each unique disease within the context of the biology of each cancer, particularly those with an “immune cold” signature like MSS/MMRp CRC.

It is also important to note that studies for patients’ chemotherapy refractory MSS/MMRp CRC revealed an important finding that liver metastases of this disease render resistance to immunotherapy [11,45]. Similar observations have also been noted for other solid tumors, including melanoma and non-small cell lung cancer metastatic to the liver, indicating a distinct pattern of immune response in this solid organ [46] A recent study suggested no significant variations in molecular alterations in liver versus lung metastasis of CRC, indicating the resistance seen with liver metastasis is likely driven by the immune microenvironment of liver parenchyma [47]. Moreover, recent studies also revealed the relatively promising response to immune checkpoint inhibitors among patients with early-stage MSS CRC [14,15]. These data suggest that tumor-hosting organs, including primary site, may have a direct impact on immune response, and some organs perhaps are linked to more immune-restrictive tumor microenvironments enabling cancer cells to grow and promote disease progression by evading the immune system. At this time, there is limited data to explain distinct responses seen in each tumor microenvironment, particularly those with liver metastases [47–49], and more translation research is warranted. So far, studies have not revealed a distinct pattern of genomic signature among patients with liver metastasis as compared to other sites of disease. Notably, dysregulation in the TGFβ pathway has been linked to the T cell exclusion from the tumor microenvironment in the liver [47,48]. Some other studies also suggest that macrophage-mediated elimination of T cells and systemic immune suppression due to circulating cytokines such as interleukin-8 may play a role in the resistance to immunotherapy [45]. Overall, the current evidence suggests the hypothesis that it may be the tumor microenvironment of the liver abrogating the antitumor immune response rather than the molecular and biological characteristics of CRC clones within the liver. More research is warranted to better define organ-specific immune response patterns and underlying molecular mechanisms, resulting in distinct outcomes seen in the studies with different sites of metastases.

7. Conclusion

Currently, biomarkers of treatment response with the use of immune checkpoint inhibitor therapy for patients with MSI-H and MSS CRC are not well defined, and they cannot be applied to daily clinical practice due to the fact that they are mostly limited to results from post-hoc analyses without prospective validation. Nonetheless, it is important to recognize the biological difference between MSI-H and MSS CRC, where the quality of mutations for neoantigen generation is highly different, yielding distinct patterns of response to immune checkpoint inhibitor therapy. Future research should consider biological differences in the tumor microenvironment of MSS and MSI-H CRC and their metastatic sites, as well as the primary site of disease, to uncover the dynamics of immune response and its temporospatial relationship with the immune microenvironment. Clinical trials investigating novel immune checkpoint inhibitors should consider rigorous correlative studies beyond known markers such as PD-L1, TMB, and CD8+ T cells to better define the therapeutic mechanisms of action of these agents, which may then provide further insight into biomarkers of response and resistance.

Funding Statement

This paper was not funded.

Article highlights

  • Unlike mismatch repair deficient (MMR-D), immune checkpoint inhibitor therapy resulted in only limited benefit among patients with mismatch repair proficient (MMR-P) colorectal cancer (CRC), indicating a biological difference mainly driven by neoantigen load.

  • Although several studies investigated potential biomarkers as potential predictors of immunotherapy response, there is no consensus for well-validated comprehensive biomarkers that can be utilized in clinical practice.

  • Tumor mutation burden (TMB), including TMB ≥ 10 mutations (mut)/Mb, and PD-L1 expression are not reliable biomarkers for MMR-P CRC. Immunoscore and Immunoscore IC, which utilize immune signatures in the tumor microenvironment, hold potential for predicting immune response for MMR-P CRC. Notably, the tumor microenvironment of early-stage MMR-P CRC appears to be more immune permissive.

  • Similar to MMR-P CRC, the tumor microenvironment of early-stage MMR-D CRC also appears to be more immune permissive, resulting in dramatic responses. TMB and neoantigen loads are potential biomarkers investigated in translational studies with relatively limited clinical use.

Author contributions

IHS and RK developed the concept of the manuscript and all authors contributed to the writing.

Disclosure statement

IHS received Advisory Board fees in Pfizer, Amgen, Seattle Genetics, GSK, Lumanity, and Clearview; Research Grants from BAYER; Speaker for Pfizer and Amgen

RK received honoraria from Incyte, Pfizer and Astra Zeneca; received consulting fee from Astra Zeneca, Bayer, Roche, Pfizer, AbbVie, Eisai, Exelixis, Merck and Ipsen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed

Writing assistance

No writing assistance was utilized in the production of this manuscript

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

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