Peptide-drug conjugates (PDCs) have emerged as a promising modality in precision oncology, enabling targeted delivery of cytotoxic payloads while minimizing off-target toxicity. The integration of covalent warheads, such as those based on sulfur(VI) fluoride exchange (SuFEx) chemistry, enhances drug-target residence time and tumor accumulation. However, existing screening methods for covalent peptide (CP) libraries require post-translational warhead conjugation, limiting throughput. Here, we present an integrated mRNA display platform that incorporates covalent warheads during ribosomal synthesis, enabling efficient screening of ultra-diverse covalent macrocyclic peptide libraries (>10¹³ variants). This approach, using site-specific incorporation of N-chloroacetyl-d-phenylalanine and fluorosulfate-l-tyrosine, accelerated the discovery of irreversibly binding (K _i = 3.58 μmol/L) Nectin-4-targeting peptide CP-N1-N₃ via proximity-triggered SuFEx. The peptide was further conjugated to cytotoxic payloads, yielding the covalent PDC CP-N1-MMAE with potent cytotoxicity (IC₅₀ ≈ 43 nmol/L) against MDA-MB-468 cells. This platform establishes a new paradigm for precision covalent drug discovery.

Purpose To analyze the clinicopathologic and immunohistochemical features, differential diagnosis and prognosis of papil-lary renal cell carcinoma (PRCC). Methods Thirty-two cases of PRCC diagnosed were reviewed. A retrospective study was per-formed including reviewing the clinical documents, pathological sections and immunohistochemical stainning and follow-up was made of 32 cases of PRCC. Twenty-one patients were treated with radical nephrectomy, eleven patients were treated with partial nephrectomy. Results Among 770 cases of renal epithelial tumors 32(4. 2%) cases of PRCC were detected. Histologically, the PRCC were charac-terized by varying proportions of papillary and tubular architecture covered by single or multiple layer of tumor cells with scanty or volu-minous basophilic or eosinophilic cytoplasm. Foam cells and psammoma bodies were seen in some papillary cores and stroma, and the cytoplasm of some tumor cells contained hemosiderin. Of these 32 patients, 18 and 14 were diagnosed type-Ⅰand type-IIPRCC, re-spectively. Type-I, with small cuboid cell and pale cytoplasm, 16 of them were low in Fuhrman grading, Type-II, with large colunmar cells, rich in eosinophilic cytoplasm, 12 of them were high in Fuhrman grading. Immunohistochemically, the PRCC showed positive immunostaining for vimentin, EMA, CK(AE1/AE3), CK7, CD10 and AMACR. All the tumors studied were negative for CK (34βE12) and TFE-3. Follow-up data were available for 31 cases, 4 patients died of cancer specific causes, 1 with type-Ⅰand 3 with type-II tumors after surgery. The other 27 patients were alive without recurrence or metastasis. High Fuhrman grading, intravascular tumor emboli, lymph node metastasis and high clinical stage were prognostic indicators in PRCC. Conclusions PRCC with unique pathological features is not a common subtype of renal cell carcinoma in China. The presence of higher nuclear grade, sarcomatoid ele-ments or clear cell carcinoma structure may indicate an aggressive biologic behavior and poor prognosis. Close attention to the cytologic and growth pattern characteristics will allow us to arrive at the proper diagnosis in most cases, although sometimes immunohistochemis-try and rarely molecular genetic evaluation may be needed.