1. Prior administration of anti-cancer immunotherapy (e.g., anti-PD-1, anti-PD-L1, anti-CTLA-4 antibody) or TGF-β targeted therapies.

2. Microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) (mandatory, locally performed), BRAFV600 mutation positive colorectal cancer (tests performed by local laboratory and per local guidelines).

3. Known complete or partial dipyrimidine dehydrogenase (DPD) enzyme deficiency (testing for DPD enzyme deficiency is not mandatory unless required by local regulations and can be conducted at a local laboratory).

4. For participants treated with irinotecan: Known history or clinical evidence of reduced UGT1A1 activity (testing for UGT1A1 status is not mandatory unless required by local regulations and can be conducted at a local laboratory).

5. Presence of symptomatic CNS metastases, or CNS metastases that requires directed therapy (such as focal radiotherapy or surgery) or increasing doses of corticosteroids 2 weeks prior to study entry. Participants with treated symptomatic brain metastases should be neurologically stable for 4 weeks post-treatment and prior to study entry, and at a dose of ≤ 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment.

6. Known history of severe allergy or hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes (e.g., monoclonal antibodies), or contraindication to any of the study drugs as outlined in the ‘Contraindications’ or ‘Warnings and Precautions’ sections of the SOC local prescribing information (e.g., Summary of Product Characteristics [SmPC], United States Prescribing Information [USPI], etc.).

7. Participant is currently receiving other anti-cancer therapy (medication or radiotherapy) or received other investigational product within 30 days or 5 half-lives prior to initiation of study treatment, whichever is longer. Note: Participants that received bevacizumab, cetuximab or panitumumab as part of the first line therapy can be enrolled before the end of 5 half-lives of these drugs

8. Participant is currently receiving any of the prohibited medications as outlined in the protocol or in the SOC anti-cancer therapy local prescribing information, and these cannot be discontinued ≥ 7 days or 5 half-lives, whichever is longer, before the first dose of study drug.

9. Participant has not recovered from a major surgery performed prior to start of study treatment or has had a major surgery within 4 weeks prior to start of study treatment.

10. Radiation therapy ≤ 4 weeks or brain-radiotherapy ≤ 4 weeks prior to start of study treatment (palliative radiotherapy to bone lesions allowed ≥ 2 weeks prior to start of study treatment).

11. Impaired cardiac function or clinically significant cardio-vascular disease, such as:

Impaired cardiac function or clinically significant cardio-vascular disease, such as:

• Congestive heart failure requiring treatment (NYHA grade ≥2), or clinically significant arrhythmia (including uncontrolled atrial flutter/fibrillation)

• Acute myocardial infarction, unstable angina pectoris, coronary stenting, or bypass surgery <6 months prior to study entry

• LVEF < 50%

• Elevated cardiac enzymes troponin I > 2 x ULN

• Cardiac valvulopathy≥ grade 2

• Uncontrolled hypertension defined by a systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥100 mm Hg

• Medical history or current diagnosis of myocarditis

12. History of positive test for human immunodeficiency virus (HIV) infection (testing is not mandatory at screening, unless if required by local regulations, where the testing will be done by local laboratory (e.g., Czech Republic)).

13. Active or chronic hepatitis B virus (HBV) or hepatitis C virus infections. Note: Participants with a history of hepatitis C virus (HCV) infection must have been treated with confirmation of cure, to be considered as eligible.

14. Active untreated or uncontrolled systemic fungal, bacterial or viral infection (including COVID-19), which in the opinion of the Investigator places the study participant at an unacceptable risk. Note: Patients with localized condition unlikely to lead to a systemic infection e.g., chronic nail fungal infection, are eligible.

15. Use of hematopoietic growth factors or transfusion support ≤ 2 weeks prior to start of study treatment.

16. Participant has conditions that are considered to have a high risk of clinically significant gastrointestinal tract bleeding, or any other condition associated with or history of significant bleeding.

17. Serious non-healing wounds.

18. Stroke or transient ischemic attack, or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 3 months before start of study treatment.

19. Concurrent malignancy other than the disease under investigation with exception of malignancy that was treated curatively and has not recurred within 2 years prior to the date of screening. Fully resected basal or squamous cell skin cancers and any carcinoma in situ are eligible.

20. Any significant medical condition, laboratory abnormality or psychiatric or social condition that would constitute unacceptable safety risks to the participants, contraindicate participant participation in the clinical study, limit the participant’s ability to comply with study requirements, or compromise participant’s compliance with the protocol and all requirements of the study as stated in the Informed Consent Form. Significant medical conditions include but are not limited to known history or current interstitial lung disease or non-infectious pneumonitis, chronic active hepatitis, liver cirrhosis or any other significant liver disease with moderate to severe hepatic impairment (Child-Pugh B or C), /ulcer/bone fracture, uncompensated/symptomatic hypothyroidism, requirement for hemodialysis or peritoneal dialysis, or uncontrolled significant deep vein thrombosis, pulmonary embolism or other clinical significant thromboembolic event.

21. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are willing to use highly effective methods of contraception during treatment with study drugs and for at least 90 days after stopping NIS793 and 120 days after stopping treatment with tislelizumab, whichever is latest. Contraception use during treatment and after stopping Standard of Care chemotherapy should be followed per the local drug label requirements and guidelines. Highly effective contraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.

• Male sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant.

• Use of oral, (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception.

• In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study treatment.

Note: Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate history of vasomotor symptoms). Women are considered not of child-bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential.

Note: Sexually active male participants and their partners who are women of childbearing potential should follow the contraception recommendations and any other precautionary measures as required by the local prescribing information for the SOC anti-cancer therapy.

Note: If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the Informed Consent Form (ICF).

22. Pregnant or breast-feeding women.

23. Use of any live/ attenuated vaccines against infectious diseases within 4 weeks of initiation of study treatment.

24. Active, known, or suspected autoimmune disease or a documented history of autoimmune disease, including ulcerative colitis and Crohn’s disease (participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll).

25. Systemic chronic steroid therapy (>10 mg/day prednisone or equivalent) or any immunosuppressive therapy for >14 days within 7 days prior to planned date for first dose of study treatment. Note: Topical, inhaled, nasal and ophthalmic steroids are allowed. For participants with adrenal insufficiency, replacement dose of >10 mg/day prednisone or equivalent are permitted.

26. History of allogeneic bone marrow or solid organ transplant