Background: Colorectal cancer is known as one of the “big killers” in oncology given its burden in terms on morbidity and mortality. Since the second half of the last century, similarly to what happened for other solid tumors, a large series of cytotoxic molecules have been developed and tested to treat this disease. Summary: Following new discoveries in terms of colorectal cancer pathogenesis and specific pathways involved such as angiogenesis, a new series of drugs have been developed: targeted therapies. Key Messages: In this review, we will briefly describe colorectal cancer molecular biology and its main pathways in order to retrace the main stages of oncological treatment development for colorectal cancer from the first available treatments to novel approaches to the disease.

Colorectal cancer (CRC) is nowadays the fourth oncological disease in terms of mortality with an estimate of almost 900,000 deaths annually worldwide. Furthermore, CRC’s incidence is predicted to increase in the upcoming years [1]. CRC development is a multistep complex process, in which accumulation of genetic mutations and epigenetic changes in cells lead to histological progression of a benign polyp into an invasive carcinoma that can be locally invasive and produce distant metastasis [2]. CRC prognosis is highly stage related: 5-year survival goes from 92% in stage 1 to 12% in stage 4. Prognosis is slightly worse in rectal cancer [3]. In this setting, during the past decades, various treatments have been developed to manage this disease: surgery, interventional endoscopy, chemotherapy, radiotherapy, immunotherapy [4]. Oncological treatment, due to advancements in pathophysiological understanding of the disease, has seen an important increase in treatment options.

Colorectal cancer results from an interaction between genetical factors and environmental factors that, through sequential stages, leads to adenoma-carcinoma transition [5]. Three main molecular pathways are involved in colorectal cancer carcinogenesis: chromosomal instability (CIN) pathway, microsatellite instability (MSI) pathway, and CpG island methylator phenotype (CIMP pathway) also known as serrated pathway [6].

  • CIN pathway: it is the most common pathway involved as it is responsible for about 65–70% of sporadic CRC. CIN is intended as the rapid change (in sense of gain or loss) in large parts of genetic material resulting in structural and numerical chromosomal anomalies in cells. This mechanism could be triggered by mutations in genes responsible for correct chromosomal segregation (such as MAD and BUB) [7]. However, the hallmark of CIN pathway is a loss-of-function mutation in the APC (adenomatous polyposis coli) gene that causes an abnormal activation of Wnt pathway. This leads to the formation of the first adenomatous cells [8]. Activation of Wnt causes a reduction in beta-catenin degradation that tends to accumulate and translocate in the nucleus where it modulates the genetic expression profile of the cell leading to an enhancement in cell proliferation. Interestingly, in tumors without APC mutation, there is often a mutation in the beta-catenin gene (CTNNB1), supporting the role of this pathway in initial stages of carcinogenesis [6]. The second main stage of CIN pathway is a mutation in the KRAS gene that produces an activated Ras protein that determines growth and progression of adenoma [9]. Activation of Ras signaling pathway leads to a cascade activation of other signaling pathways (MAPK, RAF, PI3K, RALGDS) that, in the end, determines cell proliferation and increased survival due to apoptosis resistance [7]. The third stage of CIN pathway is the acquisition of a loss-of-function mutation in TP53 gene. This causes a loss of function of p53 protein, thus leading to uncontrolled cell proliferation [6].

  • MSI pathway: MSI can be found in about 15–20% of sporadic CRC and in 95% of Lynch syndrome-related CRC [10]. MSI is defined as the presence of mutations in repetitive DNA sequence tracts (insertion or deletion of sequences) in tumoral cells, which are not present in the corresponding germ line DNA. CRC arising from MSI pathway can be divided in MSI high (MSI-H) or MSI low depending on the number of abnormal microsatellite sequences [11]. MSI is caused by a defective DNA mismatch repair (MMR) system that results from mutation or silencing of one of its constituting genes, mainly MLH1 and MSH2 [6]. In Lynch syndrome, MMR dysfunction is caused by a germline mutation in one of DNA MMR genes MLH1, MSH2, MSH6, and PMS2 [12]. In sporadic CRC, MSI is in most cases caused by an epigenetic silencing of MLH1. Other mutated genes that can be found in sporadic MSI-H CRC are BRAF, SMAD2, SMAD4, AVCR, and BAX [6].

  • CIMP pathway: CIMP pathway also known as “serrated pathway” is a colorectal cancer carcinogenetic pathway observed in serrated colorectal lesions [13]. The hallmark of this pathway is the presence of epigenetic modifications that modulate the genetic expression profile. Methylation is one of the epigenetic mechanisms regulating gene expression. In detail, methylation of CpG islands (dinucleotidic cytosine-guanine sequences) located in the promoter region of certain genes inhibits gene transcription [14]. Promoter hypermethylation can be found in 20–30% of colorectal cancers the genes involved are responsible for cell cycle regulation, apoptosis, and angiogenesis [6]. CRC can be classified in CIMP high and CIMP low depending on the degree of CpG island methylation. A CRC is considered CIMP high if at least 3 out of 5 genes analyzed present promoter hypermethylation, while a CRC that presents promoter hypermethylation in 2 or less genes analyzed is considered CIMP low [13]. Genes involved by epigenetic silencing in the CIMP pathway are p16, MGMT, TIMP3, p14, FHIT, SLC5A8. A keypoint in the serrated pathway is BRAF V600E mutation: BRAF is involved in the KRAS signaling pathway; in fact, the two mutations (BRAF and KRAS) are considered mutually exclusive in colorectal cancer. BRAF mutation leads to uncontrolled cellular growth and carcinogenesis progression [13]. BRAF mutation can be found in about 90% of CRC arising from the serrated pathway and it is related with an increased cancer-specific mortality [6].

Recently, a molecular classification system has been proposed for colorectal cancer. The classification includes 4 consensus molecular subtypes (CMSs) of CRC based on genetic expression profile: CMS1 also known as MSI immune, CMS2 also known as canonical, CMS3 also known as metabolic, and CMS4 also known as mesenchymal [15].

Conventional chemotherapy still plays a crucial role in the treatment of metastatic colorectal cancer. In fact, in the majority of patients with metastatic colorectal cancer, the first-line therapy should include a combination of conventional chemotherapeutic agents administered following specific regimens such as FOLFOX (5-fluorouracil [5-FU] + oxaliplatin + leucovorin), FOLFIRI (5-FU + irinotecan + leucovorin), and CAPOX (capecitabine + oxaliplatin) [16]. Main conventional chemotherapeutic drugs are given below.

5-Fluorouracil

Developed in 1957, 5-FU is the first chemotherapeutic agent that has been used in systemic colorectal cancer treatment [17]. 5-FU is an anti-metabolite uracil analog with a fluorine atom at the C-5 position. The anti-tumor effect depends on uracil uptake in the tumor cells. Once 5-FU is incorporated into tumor cells, it goes through a phosphorylation that produces active metabolites such as 5-fluorouridine-5′-triphosphate and 5-fluoro-2′-deoxyuridine-5′-monophosphate that have cytotoxic effects [18].

Capecitabine

Capecitabine is a fluoropyrimidine carbamate in form of prodrug that has been designed to orally administer 5-FU. Once absorbed through the intestine, capecitabine is then converted by a cascade of three enzymes (carboxylesterase, cytidine deaminase, and thymidine phosphorylase) to the active drug 5-FU that exerts cytotoxic effects [19].

Irinotecan

Irinotecan is a prodrug that is converted by a carboxylesterase to its active metabolite 7-ethyl-10-hydroxycamptothecin. This metabolite exerts its antitumor activity by inhibiting topoisomerase 1, resulting in DNA breaks and inhibition of DNA strands religation inducing replication arrest and cell death [20].

Oxaliplatin

Platinum-based drugs, including oxaliplatin, are used in the treatment of various solid tumors, including colorectal cancer. The platinum complex binds DNA and a wide range of proteins producing a cytotoxic effect by arresting cell cycle [21].

Trifluridine/Tipiracil

Trifluridine/tipiracil is an orally administered drug containing a thymidine-based nucleoside analog (trifluridine) and thymidine phosphorylase inhibitor (tipiracil). Trifluridine is responsible for the antitumor activity, while tipiracil increases its bioavailability [22]. Trifluridine is a prodrug that needs to be phosphorylated to trifluridine triphosphate to exert its activity. Trifluridine triphosphate is then incorporated into the DNA and inhibits tumor growth by interfering with DNA function [23]. In the RECOURSE trial, trifluridine/tipiracil showed superiority over placebo in terms of overall survival and progression-free survival in patients with metastatic CRC who already received other lines of therapy [24]. Following the results of the SUNLIGHT trial, ESMO recommends the trifluridine-tipiracil-bevacizumab combination as a third line of therapy in patients with mCRC who previously received fluoropyrimidines, oxaliplatin, irinotecan, and biologics [25].

Over the last decade, different molecular pathways and markers such as angiogenesis, EREG/EGFR pathway, BRAF mutation, and tyrosine kinases have been studied as possible new therapeutic targets.

  • Angiogenesis is the process by which new blood vessels are formed from pre-existing ones. During the first stages of tumor development, cell proliferation is independent from angiogenesis, while at a later stage when necrosis occurs in the central part of the tumor, an angiogenetic transition is necessary. The angiogenetic transition is the group of genetic modifications responsible for the imbalance of angiogenesis regulation in favor of pro-angiogenetic factors [26]. Vascular endothelial growth factor (VEGF) is the main regulator of angiogenesis. Its main biological function is to favor the proliferation of vascular endothelial cells and to increase vascular permeability [27]. In colorectal cancer, levels of VEGF are elevated and associated with a poor prognosis [28]. In 2004, bevacizumab was approved in the USA as a treatment for metastatic colorectal cancer. Bevacizumab is a humanized monoclonal antibody that targets soluble VEGF-A. Once bevacizumab binds to VEGF-A, it inhibits the activation of vascular endothelial growth factor receptor blocking VEGF signaling pathway and leading to inhibition of tumoral neoangiogenesis [29].

  • Epiregulin is a protein of the epidermal growth factor family. This protein binds to epidermal growth factor receptor (ErbB) family activating a pathway that regulates physiological proliferation and differentiation of normal tissues but is also involved in pathological settings such as inflammation and carcinogenesis. Receptor binding creates a homodimer or a heterodimer (dimerizing with the same kind of receptor or a different kind of receptor from the ErbB family, respectively) and activates three main pathways: Raf/Ras/MAPK pathway, PLC-gamma pathway, and PI3K/Akt pathway [30]. EGFR activation in colorectal cancer is involved in transformation of non-tumorigenic cells into cancerous cells, mitogenesis of polarizing colon cancer cells, proliferation of cancer cells, cellular metastasis, and reduction of autophagy [31]. It has been found that approximately 77% of colorectal carcinomas express EGFR [32]. Cetuximab is a monoclonal chimeric IgG1 antibody used in colorectal cancer therapy that binds to EGFR competing with other ligands and inducing an inhibition of EGFR pathway. This results in an increase of apoptosis and inhibition of cell growth and cancer invasion and metastasis [33]. Panitumumab is a fully humanized monoclonal IgG2 antibody that targets EGFR similarly to cetuximab. Its fully humanized design, however, reduces the incidence of infusions reactions [34].

  • BRAF V600E mutation, as seen in the previous paragraph, confers a poorer prognosis to CRC. Encorafenib is an ATP-competitive RAF inhibitor capable of inhibiting cell growth in CRC cells that harbor BRAF V600E mutation [35]. Currently, encorafenib is not used as a first-line therapy for mCRC, but it is used after disease progression in addition to standard systemic therapy and an EGFR inhibitor (cetuximab/panitumumab) [36].

  • Regorafenib is a multi-targeting kinase inhibitor used in mCRC in patients refractory to standard chemotherapy. It was originally designed to inhibit RAF signaling pathway, but it shows a broad-spectrum kinase inhibition pattern mainly directed toward vascular endothelial growth factor receptor, PDGFR, FGFR, RET, CSF1R, and TIE2. This confers to regorafenib anti-angiogenetic properties and an inhibiting activity on cell proliferation, metastasis, and immuno-suppression in cancer cells [37].

Immunotherapy is a group of new therapeutical strategies including adoptive cell transfer and immune checkpoint inhibitors that has been developed to direct the host immune system against cancer cells [38]. Immune checkpoints are receptors expressed by immune cells that physiologically inhibit the immune response of activated T cells. In many tumors, there is an overexpression of this immune checkpoint that confers resistance to immuno-surveillance to cancer cells [39]. Programmed death receptor (PD-1) is expressed on T-cell surface and, when activated by its ligand PD-L1, it determines the inactivation of the T cell. Tumor cells may also express PD-L1 becoming capable of maintaining immune tolerance. CTLA4 normally interacts with dendritic cell ligand B7 blocking T-cell activation at an earlier stage, and it also represents a mechanism exploited by cancer cells to obtain immune tolerance as certain neoplastic cells and cells in the tumor microenvironment may express CTLA4 [40]. Pembrolizumab is a humanized IgG4 monoclonal antibody that targets specifically PD-1 blocking its binding to PD-L1. In 2017, pembrolizumab received FDA approval for the treatment of unresectable or metastatic MSI-H colorectal cancer in patients who previously received conventional chemotherapy [41]. In 2020, pembrolizumab obtained FDA approval as first-line treatment for patients with unresectable or metastatic MSI-H or mismatch repair-deficient colorectal cancer.

Nivolumab is another humanized monoclonal antibody directed against PD-L1. Ipilimumab is a monoclonal antibody directed against CTLA4, originally developed for late-stage melanoma therapy. In 2018, the FDA approved nivolumab in monotherapy or in combination therapy with ipilimumab for the treatment of chemo-refractory (Fig. 1) MMR-D/MSI-H metastatic colorectal cancer [42].

Fig. 1.

CRC systemic therapy timeline.

Fig. 1.

CRC systemic therapy timeline.

Close modal

Recent studies have explored the possible role of specific gut microbiota alterations in carcinogenesis and chemoresistance in colorectal cancer. In particular, Fusobacterium nucleatum seems to play a role in CRC chemoresistance and thus could represent a future therapeutical target [43]. In mouse models, microbiota determines responsiveness to immune checkpoint inhibitors [44]. These advances in microbiota understanding led to the design of randomized controlled trials such as CONSORTIUM-IO (NCT04208958), an RCT that evaluates safety and efficacy of VE800 (an orally administered combination of 11 distinct bacterial strains) in combination with nivolumab in patients with metastatic CRC [45].

This brief review explores some of the historical landmarks in CRC systemic therapy. During the last decades, we have seen the development of conventional cytotoxic systemic therapies that still play a crucial role in CRC therapy. With the increasing knowledge of molecular pathways involved in CRC pathogenesis, new approaches to the disease have been discovered shifting the treatment paradigm to more targeted therapies. In the last few years, with the understanding of the role of the immune system in solid tumor carcinogenesis, there has been a further expansion of targeted therapies with the introduction of immunotherapy. Understanding of interactions between microbiota and cancer cells in carcinogenesis and in chemoresistance could lead to new therapeutical strategies.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

Chiara Pierantoni contributed to the design of the paper and to the writing of the manuscript. Lorenzo Cosentino contributed to the design of the paper and to the writing of the manuscript and designed the figure. Luigi Ricciardiello contributed to the design of the paper and supervised the project.

1.
Dekker
E
,
Tanis
PJ
,
Vleugels
JLA
,
Kasi
PM
,
Wallace
MB
.
Colorectal cancer
.
Lancet
.
2019
;
394
(
10207
):
1467
80
.
2.
Simon
K
.
Colorectal cancer development and advances in screening
.
Clin Interv Aging
.
2016
;
11
:
967
76
.
3.
Rawla
P
,
Sunkara
T
,
Barsouk
A
.
Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors
.
Prz Gastroenterol
.
2019
;
14
(
2
):
89
103
.
4.
Shinji
S
,
Yamada
T
,
Matsuda
A
,
Sonoda
H
,
Ohta
R
,
Iwai
T
, et al
.
Recent advances in the treatment of colorectal cancer: a review
.
J Nippon Med Sch
.
2022
;
89
(
3
):
246
54
.
5.
Fearon
ER
,
Vogelstein
B
.
A genetic model for colorectal tumorigenesis
.
Cell
.
1990
;
61
(
5
):
759
67
.
6.
Colussi
D
,
Brandi
G
,
Bazzoli
F
,
Ricciardiello
L
.
Molecular pathways involved in colorectal cancer: implications for disease behavior and prevention
.
Int J Mol Sci
.
2013
;
14
(
8
):
16365
85
.
7.
Pino
MS
,
Chung
DC
.
The chromosomal instability pathway in colon cancer
.
Gastroenterology
.
2010
;
138
(
6
):
2059
72
.
8.
Carethers
JM
,
Jung
BH
.
Genetics and genetic biomarkers in sporadic colorectal cancer
.
Gastroenterology
.
2015
;
149
(
5
):
1177
90.e3
.
9.
Janssen
KP
,
Alberici
P
,
Fsihi
H
,
Gaspar
C
,
Breukel
C
,
Franken
P
, et al
.
APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression
.
Gastroenterology
.
2006
;
131
(
4
):
1096
109
. (Epub 2006 Aug 16. Erratum in: Gastroenterology. 2006 Dec;131(6):2029.
10.
Grady
WM
,
Carethers
JM
.
Genomic and epigenetic instability in colorectal cancer pathogenesis
.
Gastroenterology
.
2008
;
135
(
4
):
1079
99
.
11.
Boland
CR
,
Thibodeau
SN
,
Hamilton
SR
,
Sidransky
D
,
Eshleman
JR
,
Burt
RW
, et al
.
A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer
.
Cancer Res
.
1998
;
58
(
22
):
5248
57
.
12.
Lynch
HT
,
Snyder
CL
,
Shaw
TG
,
Heinen
CD
,
Hitchins
MP
.
Milestones of Lynch syndrome: 1895-2015
.
Nat Rev Cancer
.
2015
;
15
(
3
):
181
94
.
13.
IJspeert
JE
,
Vermeulen
L
,
Meijer
GA
,
Dekker
E
.
Serrated neoplasia-role in colorectal carcinogenesis and clinical implications
.
Nat Rev Gastroenterol Hepatol
.
2015
;
12
(
7
):
401
9
.
14.
De Palma
FDE
,
D’Argenio
V
,
Pol
J
,
Kroemer
G
,
Maiuri
MC
,
Salvatore
F
.
The molecular hallmarks of the serrated pathway in colorectal cancer
.
Cancers
.
2019
;
11
(
7
):
1017
.
15.
Dienstmann
R
,
Vermeulen
L
,
Guinney
J
,
Kopetz
S
,
Tejpar
S
,
Tabernero
J
.
Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer
.
Nat Rev Cancer
.
2017
;
17
(
2
):
79
92
. (Epub 2017 Jan 4. Erratum in: Nat Rev Cancer. 2017 Mar 23;17 (4):268.
16.
Cervantes
A
,
Adam
R
,
Roselló
S
,
Arnold
D
,
Normanno
N
,
Taïeb
J
, et al
.
Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
.
Ann Oncol
.
2023
;
34
(
1
):
10
32
.
17.
Heidelberger
C
,
Chaudhuri
NK
,
Danneberg
P
,
Mooren
D
,
Griesbach
L
,
Duschinsky
R
, et al
.
Fluorinated pyrimidines, a new class of tumour-inhibitory compounds
.
Nature
.
1957
;
179
(
4561
):
663
6
.
18.
Tanaka
F
,
Fukuse
T
,
Wada
H
,
Fukushima
M
.
The history, mechanism and clinical use of oral 5-fluorouracil derivative chemotherapeutic agents
.
Curr Pharm Biotechnol
.
2000
;
1
(
2
):
137
64
.
19.
O’Neill
VJ
,
Cassidy
J
.
Capecitabine in the treatment of colorectal cancer
.
Future Oncol
.
2005
;
1
(
2
):
183
90
.
20.
Fujita
K
,
Kubota
Y
,
Ishida
H
,
Sasaki
Y
.
Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer
.
World J Gastroenterol
.
2015
;
21
(
43
):
12234
48
.
21.
Ahmad
S
.
Platinum-DNA interactions and subsequent cellular processes controlling sensitivity to anticancer platinum complexes
.
Chem Biodivers
.
2010
;
7
(
3
):
543
66
.
22.
Lenz
HJ
,
Stintzing
S
,
Loupakis
F
.
TAS-102, a novel antitumor agent: a review of the mechanism of action
.
Cancer Treat Rev
.
2015
;
41
(
9
):
777
83
.
23.
Burness
CB
,
Duggan
ST
.
Trifluridine/tipiracil: a review in metastatic colorectal cancer
.
Drugs
.
2016
;
76
(
14
):
1393
402
.
24.
Mayer
RJ
,
Van Cutsem
E
,
Falcone
A
,
Yoshino
T
,
Garcia-Carbonero
R
,
Mizunuma
N
, et al
.
Randomized trial of TAS-102 for refractory metastatic colorectal cancer
.
N Engl J Med
.
2015
;
372
(
20
):
1909
19
.
25.
Cervantes
A
,
Martinelli
E
;
ESMO Guidelines Committee
.
Updated treatment recommendation for third-line treatment in advanced colorectal cancer from the ESMO Metastatic Colorectal Cancer Living Guideline
.
Ann Oncol
.
2024
;
35
(
2
):
241
3
.
26.
Olejarz
W
,
Kubiak-Tomaszewska
G
,
Chrzanowska
A
,
Lorenc
T
.
Exosomes in angiogenesis and anti-angiogenic therapy in cancers
.
Int J Mol Sci
.
2020
;
21
(
16
):
5840
.
27.
Ferrara
N
,
Hillan
KJ
,
Gerber
HP
,
Novotny
W
.
Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer
.
Nat Rev Drug Discov
.
2004
;
3
(
5
):
391
400
.
28.
Malki
A
,
ElRuz
RA
,
Gupta
I
,
Allouch
A
,
Vranic
S
,
Al Moustafa
AE
.
Molecular mechanisms of colon cancer progression and metastasis: recent insights and advancements
.
Int J Mol Sci
.
2020
;
22
(
1
):
130
.
29.
Garcia
J
,
Hurwitz
HI
,
Sandler
AB
,
Miles
D
,
Coleman
RL
,
Deurloo
R
, et al
.
Bevacizumab (Avastin®) in cancer treatment: a review of 15 years of clinical experience and future outlook
.
Cancer Treat Rev
.
2020
;
86
:
102017
.
30.
Riese
DJ
2nd
,
Cullum
RL
.
Epiregulin: roles in normal physiology and cancer
.
Semin Cell Dev Biol
.
2014
;
28
:
49
56
.
31.
Xu
W
,
Jing
H
,
Zhang
F
.
Epidermal growth factor receptor-targeted therapy in colorectal cancer
.
Front Biosci
.
2016
;
21
(
2
):
410
8
.
32.
Yasui
W
,
Sumiyoshi
H
,
Hata
J
,
Kameda
T
,
Ochiai
A
,
Ito
H
, et al
.
Expression of epidermal growth factor receptor in human gastric and colonic carcinomas
.
Cancer Res
.
1988
;
48
(
1
):
137
41
.
33.
Fornasier
G
,
Francescon
S
,
Baldo
P
.
An update of efficacy and safety of cetuximab in metastatic colorectal cancer: a narrative review
.
Adv Ther
.
2018
;
35
(
10
):
1497
509
.
34.
Wainberg
ZA
,
Hecht
JR
.
Panitumumab in colorectal cancer
.
Expert Rev Anticancer Ther
.
2007
;
7
(
7
):
967
73
.
35.
Al-Salama
ZT
.
Encorafenib: a review in metastatic colorectal cancer with a BRAF V600E mutation
.
Drugs
.
2021
;
81
(
7
):
849
56
.
36.
Grothey
A
,
Fakih
M
,
Tabernero
J
.
Management of BRAF-mutant metastatic colorectal cancer: a review of treatment options and evidence-based guidelines
.
Ann Oncol
.
2021
;
32
(
8
):
959
67
.
37.
Arai
H
,
Battaglin
F
,
Wang
J
,
Lo
JH
,
Soni
S
,
Zhang
W
, et al
.
Molecular insight of regorafenib treatment for colorectal cancer
.
Cancer Treat Rev
.
2019
;
81
:
101912
.
38.
Zhang
Y
,
Zhang
Z
.
The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications
.
Cell Mol Immunol
.
2020
;
17
(
8
):
807
21
.
39.
Chhabra
N
,
Kennedy
J
.
A review of cancer immunotherapy toxicity: immune checkpoint inhibitors
.
J Med Toxicol
.
2021
;
17
(
4
):
411
24
.
40.
Johnson
DB
,
Nebhan
CA
,
Moslehi
JJ
,
Balko
JM
.
Immune-checkpoint inhibitors: long-term implications of toxicity
.
Nat Rev Clin Oncol
.
2022
;
19
(
4
):
254
67
.
41.
Roth
MT
,
Das
S
.
Pembrolizumab in unresectable or metastatic MSI-high colorectal cancer: safety and efficacy
.
Expert Rev Anticancer Ther
.
2021
;
21
(
2
):
229
38
.
42.
Kooshkaki
O
,
Derakhshani
A
,
Hosseinkhani
N
,
Torabi
M
,
Safaei
S
,
Brunetti
O
, et al
.
Combination of Ipilimumab and nivolumab in cancers: from clinical practice to ongoing clinical trials
.
Int J Mol Sci
.
2020
;
21
(
12
):
4427
.
43.
Yu
T
,
Guo
F
,
Yu
Y
,
Sun
T
,
Ma
D
,
Han
J
, et al
.
Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy
.
Cell
.
2017
;
170
(
3
):
548
63.e16
.
44.
Wong
CC
,
Yu
J
.
Gut microbiota in colorectal cancer development and therapy
.
Nat Rev Clin Oncol
.
2023
;
20
(
7
):
429
52
.
45.
Lu
Y
,
Yuan
X
,
Wang
M
,
He
Z
,
Li
H
,
Wang
J
, et al
.
Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies
.
J Hematol Oncol
.
2022
;
15
(
1
):
47
.