Spero Therapeutics is a clinical-stagebiopharmaceutical company focusedon identifying and developing noveltreatments for rare diseases anddiseases with high unmet need. ANNUAL REPORT 2025 UNITED STATESSECURITIES AND EXCHANGE COMMISSIONWashington, D.C. 20549FORM 10-K (Mark One) շANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934For the fiscal year ended December 31, 2025orնTRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934For the transition period from ____to____Commission file number 001-38266 SPERO THERAPEUTICS, INC.(Exact name of registrant as specified in its charter) Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. YesնNoշIndicate by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. YesնNoշ Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during thepreceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90days. YesշNoն Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T(§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). YesշNoն 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 emerginggrowth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 ofthe Exchange Act. Accelerated filerնSmaller reporting companyշEmerging growth companyն Large accelerated filerնNon-accelerated filerշ 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 revisedfinancial accounting standards provided pursuant to Section 13(a) of the Exchange Act.ն Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control overfinancial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report.ն If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect thecorrection of an error to previously issued financial statements.ն Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of theregistrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b).ն The aggregate market value of common stock held by non-affiliates of the registrant computed by reference to the price of the registrant’s common stock as of June 30,2025, the last business day of the registrant’s most recently completed second fiscal quarter, was approximately $160.3 million (based on the last reported sale price onthe Nasdaq Global Select Market as of such date). As of March 20, 2026, there were 57,891,493 shares of the registrant’s common stock, $0.001 par value per share,outstanding. DOCUMENTS INCORPORATED BY REFERENCE The registrant intends to file a definitive proxy statement pursuant to Regulation 14A relating to the 2026 Annual Meeting of Stockholders within 120 days of the end ofthe registrant’s fiscal year ended December 31, 2025. Portions of such definitive proxy statement are incorporated by reference into Part III of this Annual Report onForm 10-K to the extent stated herein. Table of Contents PART I Item 1.......................................................................................................................................................................Business4Item 1A.................................................................................................................................................................Risk Factors33Item 1B........................................................................................................................................Unresolved Staff Comments74Item 1C...............................................................................................................................................................Cybersecurity74Item 2.....................................................................................................................................................................Properties74Item 3.........