As filed with the Securities and Exchange Commission on March 23, 2026

Registration No. 333‑

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM S‑8

REGISTRATION STATEMENT

UNDER

THE SECURITIES ACT OF 1933

Xilio Therapeutics, Inc.

(Exact Name of Registrant as Specified in Its Charter)

2021 Stock Incentive Plan

2021 Employee Stock Purchase Plan

Second Amended and Restated 2022 Inducement Stock Incentive Plan

(Full Title of the Plan)

René Russo

President and Chief Executive Officer

Xilio Therapeutics, Inc.

828 Winter Street, Suite 300

Waltham, Massachusetts 02451

(Name and Address of Agent for Service)

(857) 524-2466

(Telephone Number, Including Area Code, of Agent for Service)

Copy to:

Caroline Hensley

Chief Legal Officer

Xilio Therapeutics, Inc.

828 Winter Street, Suite 300

Waltham, Massachusetts 02451

(857) 524-2466

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b‑2 of the Exchange Act.

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 7(a)(2)(B) of the Securities Act. ☐

Statement of Incorporation by Reference

This Registration Statement on Form S-8, relating to the 2021 Stock Incentive Plan (the “2021 Plan”), the 2021 Employee Stock Purchase Plan (the “2021 ESPP”), and the Second Amended and Restated 2022 Inducement Stock Incentive Plan (the “2022 Inducement Plan”) of Xilio Therapeutics, Inc. (the “Registrant”), is being filed for the purpose of registering additional securities of the same class as other securities for which a Registration Statement on Form S-8 has previously been filed and is effective. Accordingly, this Registration Statement incorporates by reference the contents of (i) the Registration Statement on Form S-8 (File No. 333-260460) filed with the Securities and Exchange Commission (“SEC”) on October 25, 2021 by the Registrant relating to the 2021 Plan and the 2021 ESPP, (ii) the Registration Statement on Form S-8 (File No. 333-263178) filed with the SEC on March 1, 2022 by the Registrant relating to the 2021 Plan and the 2021 ESPP, (iii) the Registration Statement on Form S-8 (File No. 333-270240) filed with the SEC on March 2, 2023 by the Registrant relating to the 2021 Plan, the 2021 ESPP, and the 2022 Inducement Plan, (iv) the Registration Statement on Form S-8 (File No. 333-278427) filed with the SEC on April 1, 2024 by the Registrant relating to the 2021 Plan and the 2021 ESPP, and (v) the Registration Statement on Form S-8 (File No. 333-285701) filed with the SEC on March 11, 2025 by the Registrant relating to the 2021 Plan, the 2021 ESPP, and the 2022 Inducement Plan, except, in each case, to the extent amended or superseded by the contents hereof and for “Item 8. Exhibits” with respect to which the exhibit index set forth below is incorporated herein by reference.

Item 8. Exhibits.

The following exhibits are incorporated herein by reference:

* Filed herewith

SIGNATURES

Pursuant to the requirements of the Securities Act of 1933, as amended, the registrant certifies that it has reasonable grounds to believe that it meets all of the requirements for filing on Form S‑8 and has duly caused this registration statement to be signed on its behalf by the undersigned, thereunto duly authorized, in the City of Waltham, Commonwealth of Massachusetts on this 23rd day of March, 2026.

POWER OF ATTORNEY AND SIGNATURES

We, the undersigned officers and directors of Xilio Therapeutics, Inc., hereby severally constitute and appoint René Russo and Caroline Hensley, and each of them singly (with full power to each of them to act alone), our true and lawful attorneys with full power of substitution and resubstitution in each of them for him and in his name, place and stead, and in any and all capacities, to sign for us and in our names in the capacities indicated below, the registration statement on Form S‑8 filed herewith and any and all subsequent amendments to said registration statement, and generally to do all such things in our names and on our behalf in our capacities as officers and directors to enable Xilio Therapeutics, Inc. to comply with the provisions of the Securities Act of 1933, as amended, and all requirements of the Securities and Exchange Commission, hereby ratifying and confirming our signatures as they may be signed by our said attorneys, or any of them, to said registration statement and any and all amendments thereto.

Pursuant to the requirements of the Securities Act of 1933, as amended, this registration statement has been signed by the following persons in the capacities and on the dates indicated.