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Background The CD47-SIRPα pathway is a key innate immune checkpoint that inhibits macrophage phagocytosis and contributes to T-cell exclusion, driving resistance in immunologically ‘cold’ tumors. CD47 is overexpressed in gastric cancer (GC), head and neck squamous cell carcinoma (HNSCC), and triple-negative breast cancer (TNBC). First-generation CD47 monoclonal antibodies and second-generation SIRPα-Fc fusions were limited by hematologic toxicities or insufficient efficacy. HCB101 is an SIRPα-Fc-engineered fusion protein, developed through the FBDB TM platform, designed to selectively block CD47 with minimal red blood cell binding, restoring phagocytosis, and bridging to adaptive immunity. Early monotherapy results (NCT05892718) showed a favorable safety profile and preliminary activity. Here we report results from HCB101-201 (NCT06771622), evaluating HCB101 in combination with standard therapies.Methods This ongoing multicenter, Phase Ib/IIa dose-escalation and expansion study enrolling adults with advanced solid tumors, Eastern Cooperative Oncology Group (ECOG) 0-1, and adequate organ function. Dose escalation followed a 3+3 design to assess dose-limiting toxicities (DLTs) and determine the recommended Phase 2 dose (RP2D). Cohorts included: a) second-line (2L) GC (HCB101 plus ramucirumab and paclitaxel); and b) first-line (1L) TNBC (HCB101 plus toripalimab and nab-paclitaxel). Primary endpoints were safety and tolerability; secondary endpoints included objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Exploratory endpoints assessed CD47 receptor occupancy and immune-related biomarker analyses.Results As of September 05, 2025, 12 patients were DLT-evaluable.GC cohort (n=9): 9 patients enrolled from 2.56 mg/kg to 8 mg/kg. One DLT (Grade 4 thrombocytopenia at 8 mg/kg) recovered with supportive care. Common treatment-related adverse events (TRAEs) included anemia (72.7%) and cytopenias (18.2%~72.7%). At 2.56 mg/kg (n=3), all evaluable participants achieved stable disease (SD). At 5.12 mg/kg (n=3), all participants achieved confirmed partial responses (PRs) with tumor shrinkage of 33%~46%. At 8.00 mg/kg (n=3), two confirmed PRs with tumor shrinkage of 78% and 31% were observed; the third participant remains under evaluation.TNBC cohort (n=3): At 2.56 mg/kg,Conclusions HCB101 in combination with standard therapies demonstrated manageable safety and clear dose-dependent antitumor activity in advanced GC and TNBC, with confirmed partial responses emerging at clinically relevant doses. The differentiated safety profile and observed efficacy contrast with the limitations of earlier CD47-targeting agents. These findings support ongoing expansion cohorts and further investigation of HCB101-based combinations as a strategy to reprogram immunologically cold tumors and improve outcomes in difficult-to-treat cancers.Trial Registration This trial is registered on clinicaltrials.gov. NCT06771622Ethics Approval The study was approved by following ethics committees: 1.Cancer Hospital of Shandong First Medical University Ethics Committee; Number of theapproval: SDZLEC2024-412-04; 2.The Fifth Affiliated Hospital, Sun Yat-sen University Ethics Committee; Number of the approval:2025-Y241-3; 3.Dongguan People’s Hospital Ethics Committee; Number of the approval: DRYA2025-015-B3; 4.Qilu Hospital of Shandong University Dezhou Hospital Ethics Committee; Number of the approval: 2025-003-002; 5.Binzhou Medical University Affiliated Hospital Ethics Committee; Number of the approval: 2025-011-03;Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.